@article {pmid40935607,
year = {2025},
author = {Yoo, HB and Kang, SK and Shin, SA and Kim, D and Choi, H and Kim, YK and Yi, D and Byun, MS and Lee, DY and Lee, JS and , },
title = {Artificial Intelligence-Powered Quantification of Flortaucipir PET for Detecting Tau Pathology.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.269636},
pmid = {40935607},
issn = {1535-5667},
abstract = {We developed and evaluated an artificial intelligence (AI)-powered approach for easier quantification of tau PET uptake without requiring structural MR to aid earlier tracking of Alzheimer disease (AD). Methods: We implemented a deep neural network model that normalizes [18]F-AV1451 (tau) PET images to a standard template without requiring MR, using transfer learning from a model pretrained on amyloid PET. This model was integrated into an MR-free pipeline for tau PET quantification and validated on external dataset (Alzheimer Disease Neuroimaging Initiative). We examined correlations between model-derived tau uptake estimates and cognitive measures, including AD stage and episodic memory performance (n = 666). Longitudinal analyses were conducted to assess whether baseline tau deposition predicted future cognitive decline (n = 168). Results: The AI-powered pipeline achieved robust performance with intraclass correlation coefficients exceeding 0.97 for regional uptake estimation compared with MR-based ground truth. We also showed that the tau deposition in metatemporal regions was significantly correlated with Mini-Mental State Examination and Montreal Cognitive Assessment scores. Elevated tau PET uptake in the entorhinal cortex and inferior temporal gyrus predicted future cognitive decline. Conclusion: The proposed AI-powered pipeline enhances the clinical accessibility of tau PET by reducing scan costs and streamlining the uptake quantification, achieving high performance without requiring structural MR. We further demonstrated that the pipeline yields cognitively relevant outcome measures for early diagnosis and monitoring of AD progression to aid more personalized treatment strategies targeting AD biomarkers.},
}

@article {pmid40935215,
year = {2025},
author = {Huang, H and Lu, W and Huang, Y and Su, Y and Luo, R and Zeng, Y and Yuan, C and Jia, Z and Wang, X},
title = {Bazi Bushen improves cognitive dysfunction in 5×FAD mice by targeting amyloid pathology, neuroinflammation and cellular senescence.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120586},
doi = {10.1016/j.jep.2025.120586},
pmid = {40935215},
issn = {1872-7573},
abstract = {Bazi Bushen (BZBS), a Traditional Chinese Medicine (TCM) formula, is composed of fourteen herbal ingredients, including classic tonics such as Ginseng Radix et Rhizoma and Cistanches Herba. Traditionally used to combat fatigue and promote vitality in aging individuals, BZBS is rooted in TCM principles of kidney essence replenishment and brain function enhancement. Recent pharmacological studies have begun to validate its efficacy in age-related cognitive decline, but its effects and mechanisms in Alzheimer's disease (AD) remain unclear.

AIM OF THE STUDY: This study aimed to evaluate the potential therapeutic effects of BZBS in 5×FAD transgenic mice, a commonly used Alzheimer's disease model, and to shed light on its possible mechanisms of action.

METHODS: Four- and six-month-old 5×FAD mice were treated with BZBS to examine how it might influence cognitive performance. Behavioral assessments were carried out using Y-Maze and the Morris Water Maze. To investigate the biological changes and uncover the mechanisms involved, we used a range of techniques-Thioflavin S staining, immunofluorescence, Western blotting, and qPCR-to look at Aβ plaque accumulation, Amyloid Precursor Protein C-terminal Fragments (APP-CTF) and β-secretase 1 (BACE1) expression levels, markers of inflammation, and indicators of cellular aging in hippocampus and motor cortex.

RESULTS: In the 4-month group, where treatment was started before severe pathology developed, BZBS improved learning and memory performance. It also reduced amyloid deposition in the cortex and hippocampus, and lowered the levels of APP-CTFs and BACE1. In addition, we observed decreased mRNA expression of IL-1α, IL-6, and NF-κB, along with reduced microglial activation in the hippocampus of BZBS-treated mice. Similarly BZBS downregulated key markers of cellular senescence, including p16, p21, and senescence-associated β galactosidase (SA-β-gal) activity. In the 6-month group, which already showed signs of amyloid pathology, BZBS still had beneficial effects-improving cognition, lowering Aβ load, and reducing microglial activity-suggesting that it may be effective even after disease onset.

CONCLUSION: These findings demonstrate that BZBS exerts significant therapeutic effects in 5×FAD mice, including improved cognitive improvement, reduced Aβ deposition, suppressed microglial activation, and attenuated hippocampal cellular senescence. Notably, BZBS was effective whether administered from the early stage of pathology (at four months of age) or after established amyloidosis (at six months of age), highlighting its dual potential as both a preventive and disease-modifying intervention for Alzheimer's disease (AD).},
}

@article {pmid40935202,
year = {2025},
author = {Yang, X and Hu, D and Zhao, S and Wan, J and Chen, L and Bao, Q and Zhang, Y and Wang, Q and Huang, Z},
title = {Neuroprotective Effects of Butyrolactone II from Aspergillus terreus via Nrf-2/SKN-1 Pathway Modulation in Caenorhabditis elegans.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110107},
doi = {10.1016/j.jnutbio.2025.110107},
pmid = {40935202},
issn = {1873-4847},
abstract = {Fourteen compounds were isolated from the fermentation broth of Aspergillus terreus, all of which were isolated from A. terreus for the first time. Among them, butyrolactone II (A9) had excellent DPPH radical scavenging activity, with an EC50 value of 42.05 μM superior to positive control drug BHT. Further neuroprotective activity evaluation of in Caenorhabditis elegans CL2355 revealed that butyrolactone II could alleviate Aβ, causing chemotaxis disorder, prolonging lifespan of C. elegans, and reducing 5-HT sensitivity. Butyrolactone Ⅱ treatment significantly elevated the chemotaxis index of genotyped nematode CL2355 by 15.06% (P<0.05), and reduced the sensitivity of nematodes to 5-HT, decreasing the paralysis rate by 9.8% (P<0.05). Moreover, it significantly increased median lifespan and maximum lifespan by 20% and 26% respectively. In the RNA transcriptome, Butyrolactone II caused upregulation of 277 differentially expressed genes and downregulation of 171 differentially expressed genes, inducing the entry of transcription factor SKN-1 into the nucleus and changes in its downstream genes. The annotation and enrichment of GO and KEGG pathways indicated that differentially expressed genes might be related to pathways such as metabolic detoxification, oxidative stress, and lysosomal autophagy. The qRT-PCR validation of gene expression was consistent with transcriptomics. Butyrolactone II could significantly increase the expression of mitochondrial fission factor (mff-2), downstream genes related to SKN-1 (dod-17, gst-38), heat shock protein genes (hsp-17, hsp-12.6), and oxidative stress related genes (cyp-14A5) in nematodes, while having no significant effect on the expression level of gst-33 gene. Taken conclusion, butyrolactone II exerts neuroprotective effects by modulating the Nrf-2/SKN-1 pathway and regulating metabolic pathways, underscoring its potential as a therapeutic strategy for Alzheimer's disease and other related neurodegenerative disorders.},
}

@article {pmid40934766,
year = {2025},
author = {Xin, X and Zong, T and Hu, Z and Jin, L and Zhou, W and Sun, J and Li, G},
title = {Discovery of natural compounds and their derivatives against neuroinflammation: Pharmacological mechanisms and structure-activity relationship.},
journal = {Bioorganic chemistry},
volume = {165},
number = {},
pages = {108934},
doi = {10.1016/j.bioorg.2025.108934},
pmid = {40934766},
issn = {1090-2120},
abstract = {Neuroinflammation refers to the inflammatory response within the central nervous system mediated by immune and glial cells, constitutes a pivotal mechanism in the pathological progression of neurodegenerative diseases. Alzheimer's disease (AD) serves as a paradigmatic example of neuroinflammation role in driving cytokine-mediated neuronal damage and perpetuating of disease progression. AD, which is characterized by memory decline and progressive cognitive impairment as its core clinical manifestations, currently has no effective treatment. Recent advances have underscored natural products as promising candidates for the development of safer and more effective anti-AD agents, particularly through the targeting of neuroinflammatory pathways that have emerged as central pathological mechanisms in the progression of AD. This review aims to elucidate the pathogenesis of neuroinflammation in AD and provides a comprehensive overview of anti-AD drugs currently in clinical research as well as those already available on the market. Additionally, this paper highlights natural compounds and their derivatives discovered over the past decade that exhibit anti-AD neuroinflammatory properties, analyzing the structure-activity relationships of selected compounds and their permeability across the blood-brain barrier. The goal is to offer valuable insights and references for drug developers.},
}

@article {pmid40934542,
year = {2025},
author = {Liu, T and Zhang, W and Bao, W and Wang, X and Zhang, F and Guo, J and Li, M},
title = {Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages.},
journal = {International immunopharmacology},
volume = {165},
number = {},
pages = {115526},
doi = {10.1016/j.intimp.2025.115526},
pmid = {40934542},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is associated with progressive bone loss, but the underlying mechanisms remain unclear. This study focused on how amyloid-β (Aβ) disrupted bone vascular homeostasis by impairing macrophage efferocytosis in APP/PS1 mice. We found that Aβ accumulation in bone tissue impaired MerTK-mediated macrophage efferocytosis and promoted excessive accumulation of apoptotic endothelial cells (ECs). Mechanistically, Aβ triggered excessive mitochondrial fission via GSK-3β-mediated DRP1 phosphorylation, resulting in elevated reactive oxygen species (ROS) and subsequent ADAM17 activation. ADAM17 cleaved MerTK, a critical efferocytosis receptor, impairing apoptotic cells (ACs) clearance. Pharmacological inhibition of GSK-3β (LiCl and TDZD-8) or mitochondrial fission (Mdivi-1) restored MerTK expression, improved efferocytosis, and reduced inflammatory cytokine release (such as TNF-α, IL-6), while enhancing vascular endothelial growth factors (VEGFs). In vivo, LiCl treatment ameliorated bone loss and vascular dysfunction in APP/PS1 mice. These findings revealed that Aβ disrupted the mitochondrial fission-efferocytosis axis in macrophages, contributing to AD-related bone pathology, and highlighted GSK-3β as a potential therapeutic target for preserving bone vascular homeostasis in AD.},
}

@article {pmid40933919,
year = {2025},
author = {Song, B and Yue, D and Yan, H and Feng, L and Li, M},
title = {Traditional Chinese Medicine Natural Products Targeting Shared Mechanisms of T2DM and AD: Potential Therapeutic Insights.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {7681-7705},
doi = {10.2147/DDDT.S531909},
pmid = {40933919},
issn = {1177-8881},
abstract = {As highly prevalent chronic diseases globally, AD (Alzheimer's disease) and T2DM (type 2 diabetes mellitus) not only severely affect the quality of life of patients but also impose a significant burden on their families. Numerous studies have gradually revealed that T2DM and AD are bidirectional risk factors, each capable of exacerbating the other. There is a notable correlation in their pathological mechanisms, primarily manifested in insulin resistance, OS (oxidative stress), and inflammatory responses. Currently, available drugs can only delay the progression of AD, such as Donepezil, Galantamine, and Carbamylcholine, making complete cures challenging to achieve. TCM (Traditional Chinese medicine) natural products exhibit characteristics such as multi-targeting, multi-pathway interactions, diverse biological activities, and relatively mild side effects, enabling synergistic intervention in both diseases. In recent years, TCM natural products have garnered increasing attention in research concentrated on the prevention and management of AD and T2DM. This article aims to comprehensively elucidate the collective pathogenic mechanism of AD and T2DM, and explore the progress of TCM natural products based on these mechanisms in the prevention and treatment of both diseases, thereby providing a theoretical foundation for the advancement of innovative treatment tactics.},
}

@article {pmid40933857,
year = {2025},
author = {Li, H and Zhu, J and Li, J and Wu, Y and Luo, C and Huang, Y and Wu, J and Liu, W and Wang, H and Mo, Z},
title = {Human brain organoids: an innovative model for neurological disorder research and therapy.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1658074},
doi = {10.3389/fncel.2025.1658074},
pmid = {40933857},
issn = {1662-5102},
abstract = {The emergence of human brain organoids (hBOs) has transformed how we study brain development, disease mechanisms, and therapy discovery. These 3D in vitro neural models closely mimic the cellular diversity, spatial structure, and functional connectivity of the human brain, providing a groundbreaking platform that outperforms traditional 2D cultures and animal models in studying neurodevelopment and neurological disorders. To further explore the potential of hBOs technology, we review current literature focusing particularly on its applications for diagnosing and treating major neurological diseases such as Alzheimer's disease, Parkinson's disease, and other related neurological disorders. Using patient-derived induced pluripotent stem cells combined with cutting-edge gene-editing technologies, hBOs enable highly precise mechanistic studies and scalable drug screening. Moreover, we further discuss the advantages and current limitations of hBOs. Despite these challenges, hBOs remain a transformative platform for the development of targeted neurotherapeutics. Collectively, this review offers a solid foundation for advancing neuroscience research and fostering innovative treatment strategies for neurological disorders.},
}

@article {pmid40933625,
year = {2025},
author = {Hean, AC and Jones, J and Arena, M and Kavanagh, K},
title = {Memantine leading to physical aggression in the treatment of chronic catatonia secondary to schizophrenia: A case report.},
journal = {The mental health clinician},
volume = {15},
number = {4},
pages = {218-221},
doi = {10.9740/mhc.2025.08.218},
pmid = {40933625},
issn = {2168-9709},
abstract = {INTRODUCTION: Memantine is a noncompetitive N-methyl-D-aspartate receptor antagonist approved by the FDA for moderate to severe Alzheimer's dementia. Memantine is also recommended as an off-label treatment in current catatonia clinical guidelines when benzodiazepines alone are inadequate.

CASE: A 37-year-old male with a history of schizophrenia on psychiatric conservatorship, stimulant use disorder, and traumatic brain injury was stabilized on risperidone 4 mg twice daily, diphenhydramine 50 mg twice daily, divalproex delayed release 500 mg twice daily, and lorazepam 1 mg twice daily for catatonia. Lorazepam was titrated for unresolved chronic catatonic symptoms but was not tolerated beyond 5 mg total per day due to hemodynamic instability. Owing to barriers in initiating clozapine or electroconvulsive therapy, the patient was started on memantine to address residual catatonia symptoms. After the addition of memantine, the patient began to spontaneously speak in multiple languages and engage in discharge planning, but shortly after a dose increase to 15 mg daily also displayed increased aggressive behaviors. The aggression improved after decreasing the dose to 10 mg daily, and the patient was discharged.

CONCLUSIONS: This case adds to the body of evidence for memantine in catatonia with underlying schizophrenia and, to our knowledge, is the first described case of memantine uncovering aggression during catatonia treatment.},
}

@article {pmid40933191,
year = {2025},
author = {Zhao, Y and Wang, X and Zhang, J and Zhao, Y and Li, Y and Shen, J and Yuan, Y and Li, J},
title = {Plasma FGF2 and YAP1 as novel biomarkers for MCI in the elderly: analysis via bioinformatics and clinical study.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1663276},
doi = {10.3389/fnins.2025.1663276},
pmid = {40933191},
issn = {1662-4548},
abstract = {The contemporary consensus firmly emphasizes the urgent need to reorient research efforts toward the early detection of preclinical Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, there is still a notable absence of novel biomarkers that are both efficient, minimally invasive, and cost-effective in real-world clinical settings. To address this gap, datasets GSE29378 and GSE12685 were selected to screen differentially expressed genes (DEGs), and hub genes were identified by different algorithms. A total of 350 DEGs were identified in bioinformatics data mining. Functional enrichment analysis showed that fibroblast growth factor 2(FGF2) and yes-associated protein 1(YAP1) protein levels were highly expressed in AD samples, indicating their potential regulatory roles in AD. Between October and November 2024, a total of 146 elderly individuals diagnosed with MCI and 54 healthy elderly subjects were successfully recruited. Enzyme linked immunosorbent assay (ELISA) was used to detect plasma hub gene protein concentration. The results showed that the expression levels of plasma FGF2 and YAP1 proteins in the MCI group were significantly higher compared to the control group. Logistic regression analysis indicated that high plasma FGF2 and YAP1 expression levels were independently associated with MCI in the elderly. The Area under the curve (AUC) of FGF2 model and YAP1 model were 0.907 and 0.972, respectively. Therefore, the high expression of plasma FGF2 and YAP1 proteins may be independent predictive risk factors for MCI in the elderly. Our findings may provide targets for the development of early minimally invasive, efficient, and convenient screening tools, and even for the treatment of AD in the future.},
}

@article {pmid40933041,
year = {2025},
author = {He, C and Chen, B and Yan, C and Zhou, X},
title = {Stem cell and CRISPR/Cas9 gene editing technology in Alzheimer's disease therapy: from basic research to clinical innovation.},
journal = {Frontiers in genome editing},
volume = {7},
number = {},
pages = {1612868},
doi = {10.3389/fgeed.2025.1612868},
pmid = {40933041},
issn = {2673-3439},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by Aβ plaques, tau protein neuronal fiber tangles, and neuroinflammation, poses a significant global health problem, and current therapies focus on the symptoms rather than the cause. This paper gives a new multidimensional therapeutic form to AD treatment by exploring the integrated application of stem cell therapy and CRISPR/Cas9 gene editing technology. The study comprehensively dissected the roles of neural stem cells (NSCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) in neural replacement, neuroinflammation modulation and neuroplasticity enhancement, and also explored the application of CRISPR/Cas9 in modifying the pathogenic variants of AD-related genes (APP, PSEN1 and PSEN2). The key findings suggest that gene-edited iPSCs can reduce abnormal Aβ and tau protein accumulation in AD models, improve cognitive function, and provide a platform for disease modeling and drug screening. Stem cell transplantation promotes neurogenesis and synaptic plasticity by secreting neurotrophic factors to improve the brain microenvironment. Despite the challenges of off-target effects, immune rejection, and long-term safety, the synergistic application of these two technologies offers a breakthrough solution for AD treatment. This paper highlights the translational potential of combining stem cells with gene editing technology, which is expected to drive clinical applications in the next 5-10 years. The integration of these advanced technologies not only addresses the limitations of current AD treatments, but also paves the way for a personalized medical approach that is expected to revolutionize the AD treatment landscape and bring new hope to patients worldwide.},
}

@article {pmid40932994,
year = {2025},
author = {Katel, S and Cicalo, J and Vasciaveo, V and Vecchio, LM and Carrion, J and Mahadeo, L and Huerta, PT and Choksi, JD and Aubert, I and Marambaud, P and Giliberto, L and d'Abramo, C},
title = {AAV-mediated peripheral scFv's administration to reduce cerebral tau in adult P301S transgenic mice: Mono-vs. combination therapy.},
journal = {Molecular therapy. Methods & clinical development},
volume = {33},
number = {3},
pages = {101563},
doi = {10.1016/j.omtm.2025.101563},
pmid = {40932994},
issn = {2329-0501},
abstract = {Tau is a primary target for immunotherapy in Alzheimer's disease (AD). Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFvs) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in 8-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric, and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for AD. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies' combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone.},
}

@article {pmid40931963,
year = {2025},
author = {Nardi Cesarini, E and Falcicchio, G and Librizzi, L and Sciaccaluga, M and Assenza, G and Galimberti, CA and Giorgi, FS and DiFrancesco, JC and Costa, C and , },
title = {Etiological diagnosis of late-onset epilepsy: A key priority for Italian epileptologists - Insights from a LICE survey.},
journal = {Epilepsia open},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi4.70131},
pmid = {40931963},
issn = {2470-9239},
abstract = {OBJECTIVE: The incidence of epilepsy rises markedly after age 50. While late-onset epilepsy (LOE) is often linked to structural brain abnormalities, non-structural factors, such as infections, autoimmune disorders, and neurodegenerative diseases, also contribute. Approximately 20% of LOE cases remain of unknown etiology (LOEU). This study evaluated the diagnostic and therapeutic strategies employed by Italian epileptologists in managing LOE and LOEU, with the ultimate goal of proposing a standardized diagnostic algorithm.

METHODS: Data were collected through a cross-sectional online survey administered to neurologists who are formal members of the Italian Chapter of the International League Against Epilepsy (LICE). Descriptive statistics were used to summarize responses, and inferential statistics were applied to derive meaningful conclusions.

RESULTS: Sixty-five epilepsy centers across 19 of the 20 Italian regions participated in the survey. EEG (100%; n = 65) and brain MRI (92.31%; n = 60) were routinely employed in the diagnostic evaluation of LOE. In over half of the centers (58.46%; n = 38), sleep-activated or sleep-influenced EEGs were also used. For LOEU cases, neuropsychological assessments were performed in 60% of centers. More than 30% of centers employed additional diagnostic tools, including lumbar puncture, FDG-PET, and serum antibody testing for neural autoantibodies. The most commonly prescribed anti-seizure medications (ASMs) for LOE were levetiracetam (86.15%; n = 56), lacosamide (81.54%; n = 53), and lamotrigine (61.54%; n = 40).

SIGNIFICANCE: These findings suggested that Italian epileptologists frequently evaluate patients with LOE during routine outpatient visits. LOEU is increasingly recognized as a distinct subtype of LOE that may warrant a targeted diagnostic approach due to the potential involvement of autoimmune and neurodegenerative mechanisms. There is a pressing need for focused cross-sectional or prospective multicenter studies to refine the diagnostic strategies for LOE, particularly for LOEU, and to enhance the characterization of its clinical and etiological features.

PLAIN LANGUAGE SUMMARY: After age 50, epilepsy rates rise, often linked to brain changes but sometimes with no clear cause (LOEU). We surveyed Italian epilepsy specialists and found that routine EEG and MRI are widely used, yet about 20% of cases require advanced tests to identify rare or autoimmune causes. Our findings will inform patient-focused diagnostic and treatment guidelines and underscore the need for standardized care pathways and further research in adult-onset epilepsy.},
}

@article {pmid40931717,
year = {2025},
author = {Rogers, EA and Diorio, TC and Beauclair, T and Martinez, J and Mufti, SJ and Kim, D and Krishnan, N and Rayz, V and Shi, R},
title = {Concussive injuries induce neuronal stress-dependent tau mislocalization to dendritic spines with acrolein and functional network alteration in TBI-on-a-chip.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
pmid = {40931717},
issn = {1473-0189},
abstract = {Traumatic brain injuries (TBIs) are a risk factor for Alzheimer's disease (AD), and share several important pathological features including the development of neurofibrillary tangles (NFT) of tau protein. While this association is well established, the underlying pathogenesis is poorly defined and current treatment options remain limited, necessitating novel methods and approaches. In response we developed "TBI-on-a-chip", an in vitro trauma model utilizing murine cortical networks on microelectrode arrays (MEAs), capable of reproducing clinically relevant impact injuries while providing simultaneous morphological and electrophysiological readout. Here, we incorporate a digital twin of the TBI-on-a-chip model to resolve cell-scale mechanical deformation via shear stresses and demonstrate direct connections between impact forces with aberrations in tau and synaptic deficits, and correlate these changes with elevations of oxidative stress, a suspected key contributor to both trauma and neurodegeneration. This multi-disciplinary investigation combines computational modeling, electrophysiology, and imaging, to explore tau mislocalization and functional deficits as a function of force, in the context of a potential mechanism via acrolein. We hope that this novel, integrative approach will help improve our mechanistic understanding of trauma and neurodegeneration, solo and in concert, and ultimately assist in generating more effective treatment options.},
}

@article {pmid40931680,
year = {2025},
author = {Stone, WJ and Pair, FS and Ekkatine, R and Gannon, M and Scholz, K and Pattanayak, R and Syed, R and Yacoubian, TA},
title = {14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.},
journal = {Journal of neurochemistry},
volume = {169},
number = {9},
pages = {e70228},
doi = {10.1111/jnc.70228},
pmid = {40931680},
issn = {1471-4159},
support = {//Parkinson Association of Alabama/ ; F31ES034985/NH/NIH HHS/United States ; R01NS112203/NH/NIH HHS/United States ; },
mesh = {*Microglia/metabolism/drug effects ; *14-3-3 Proteins/metabolism/antagonists & inhibitors ; Animals ; Mice ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Signal Transduction/physiology/drug effects ; Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {Microglia, the resident immune cells of the central nervous system (CNS), are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson's disease (PD). 14-3-3 proteins act as molecular hubs to regulate protein-protein interactions, which are involved in numerous cellular functions, including cellular signaling, protein folding, and apoptosis. We previously revealed decreased 14-3-3 levels in the brains of human subjects with neurodegenerative diseases. In this study, we examined the role of 14-3-3 proteins in the microglial proinflammatory response to lipopolysaccharide (LPS). We found that LPS treatment induced 14-3-3 protein levels within 6 hours. With the use of BV02 and dimeric fourteen-three-three peptide inhibitor (difopein), a small molecule and peptide inhibitor of 14-3-3 protein-protein interactions, respectively, we found a dramatic increase in microglial activation markers in both immortalized BV-2 microglial cells and in primary mouse microglia. Both 14-3-3 inhibitors also increased LPS-induced microglial phagocytosis, lysosomal proteolysis, and cytokine release in primary microglia. In contrast, chemotaxis toward the cellular damage stimulus, adenosine triphosphate (ATP), was diminished with 14-3-3 inhibition. Inhibition of 14-3-3's hastened LPS-induced activation of the nuclear factor-kB (NF-κB) signaling pathway, as measured by its nuclear translocation. 14-3-3's reduced activation of the NF-κB pathway by binding and inhibiting the release of IκB kinase beta (IKKβ). Disruption of 14-3-3's binding to IKKβ with BV02 or difopein increased the downstream phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα). Collectively, our findings suggest 14-3-3 proteins play a critical role in the regulation of inflammatory responses in microglia and may serve as potential targets for immunotherapy of CNS diseases.},
}

*Microglia/metabolism/drug effects
*14-3-3 Proteins/metabolism/antagonists & inhibitors
Animals
Mice
*NF-kappa B/metabolism/antagonists & inhibitors
*Signal Transduction/physiology/drug effects
Lipopolysaccharides/pharmacology
Mice, Inbred C57BL
Cells, Cultured

@article {pmid40931498,
year = {2025},
author = {Alemán-Villa, KM and Armienta-Rojas, DA and Camberos-Barraza, J and Rábago-Monzón, ÁR and Camacho-Zamora, A and Osuna-Ramos, JF and Magaña-Gómez, JA and Guadrón-Llanos, AM and Calderón-Zamora, L and Norzagaray-Valenzuela, CD and Valdez-Flores, MA and Picos-Cárdenas, VJ and De la Herrán-Arita, AK},
title = {Neuroinflammation across the spectrum of neurodegenerative diseases: mechanisms and therapeutic frontiers.},
journal = {Neuroimmunomodulation},
volume = {},
number = {},
pages = {1-33},
doi = {10.1159/000548021},
pmid = {40931498},
issn = {1423-0216},
abstract = {Neuroinflammation has emerged as a central and dynamic component of the pathophysiology underlying a wide range of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Far from being a secondary consequence of neuronal damage, inflammatory processes (mediated by microglia, astrocytes, peripheral immune cells, and associated molecular mediators) actively shape disease onset, progression, and symptomatology. This review synthesizes current knowledge on the cellular and molecular mechanisms that govern neuroinflammatory responses, emphasizing both shared and disease-specific pathways. We examine how innate and adaptive immune interactions contribute to neuronal vulnerability and neurodegenerative cascades, and explore the reciprocal communication between systemic and central immune compartments. Particular attention is given to emerging therapeutic strategies aimed at modulating neuroinflammation, including immunomodulatory drugs, glial-targeted interventions, and novel delivery platforms. By integrating findings across disciplines and disease models, we outline key translational challenges and propose future directions to harness neuroinflammation as a therapeutic target in the era of precision medicine. Ultimately, a deeper understanding of neuroimmune dynamics holds promise for redefining both the diagnosis and treatment of neurodegenerative disorders.},
}

@article {pmid40931359,
year = {2025},
author = {Ramonet, D and Daerr, A and Hallbeck, M},
title = {Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer's disease mouse model.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {190},
pmid = {40931359},
issn = {2051-5960},
support = {2019-01016//Swedish Research Council/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/drug therapy ; Mice ; *Endosomes/metabolism/drug effects/pathology ; Disease Models, Animal ; *Synapses/metabolism/drug effects/pathology ; Mice, Transgenic ; *Vesicular Transport Proteins/metabolism/genetics ; Protein Transport/drug effects/physiology ; Humans ; },
abstract = {Disruptions in synaptic transmission and plasticity are early hallmarks of Alzheimer's disease (AD). Endosomal trafficking, mediated by the retromer complex, is essential for intracellular protein sorting, including the regulation of amyloid precursor protein (APP) processing. The VPS35 subunit, a key cargo-recognition component of the retromer, has been implicated in neurodegenerative diseases, with mutations such as L625P linked to early-onset AD. Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood. Here, we investigate the acute molecular effects of retromer stabilization in the 5xFAD mouse model of AD using the pharmacological chaperones R55 and R33, previously identified to enhance VPS35 stability. Following intracranial stereotaxic injections, we performed transcriptomic profiling, quantitative histology, and immunohistochemistry to assess synaptic function, neuroinflammation, and endosomal trafficking. Our findings reveal that retromer stabilization reverses multiple AD-associated molecular changes. R55 treatment significantly reduced Aβ-related pathology, normalized synaptic gene expression, and restored long-term potentiation (LTP)-associated pathways, including Gria1 (AMPA receptors), Grip1, and semaphorin/plexin signaling. Additionally, retromer stabilization counteracted dysregulated calcium signaling by modulating Ryr2 and L-type calcium channel expression. Beyond synaptic effects, we observed broad transcriptional and structural changes in the endosomal system. Notably, R55 treatment decreased VPS13 family gene expression, implicated in membrane contact site regulation, while increasing RAB7 levels, suggesting enhanced late-endosomal recycling. VPS35-positive vesicles were redistributed away from the nucleus, indicating restored intracellular trafficking dynamics. In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes. Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis. Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics/drug therapy
Mice
*Endosomes/metabolism/drug effects/pathology
Disease Models, Animal
*Synapses/metabolism/drug effects/pathology
Mice, Transgenic
*Vesicular Transport Proteins/metabolism/genetics
Protein Transport/drug effects/physiology
Humans

@article {pmid40931113,
year = {2025},
author = {Hu, M and Kang, X and Liu, Z and Wang, S and Liu, S and Li, C and Lu, D and Qin, Q and Liu, Y and Yi, H and Yuan, L and Liu, Q and Lu, Z and Cai, W},
title = {Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {40931113},
issn = {2662-8465},
support = {82271348//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment with Tspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy.},
}

@article {pmid40930236,
year = {2025},
author = {Zhang, F and Ding, K and Zhang, LM and Liu, DY and Dong, X and Wang, MN and Zhou, FL and Sun, YW and Zhang, WK and Yan, Y and He, J and Xu, JK},
title = {The role of the gut microbiota in neuropsychiatric disorders and therapy.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102894},
doi = {10.1016/j.arr.2025.102894},
pmid = {40930236},
issn = {1872-9649},
abstract = {The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD), collectively affect over one billion individuals globally. Emerging scientific evidence has consistently demonstrated the presence of GM dysbiosis in various neuropsychiatric disorders, suggesting a potential etiological role of GM in these conditions through MGBA-mediated mechanisms. In this comprehensive review, we systematically discussed the GM and MGBA, and presented evidence from both animal and human studies that highlighted the significance of GM in the occurrence and development of neuropsychiatric disorders. Subsequently, we emphasized the potential impact of GM and its metabolites on neuropsychiatric disorders. Next, we summarized the drugs used to treat diseases by regulating the GM. Finally, we proposed strategies to ameliorate the malignant progression of neuropsychiatric disorders by manipulating the composition of the GM. These strategies encompass the application of probiotics, prebiotics and synbiotics, postbiotics, fecal microbiota transplantation (FMT), dietary interventions. Collectively, targeted GM therapy has the potential to be an effective treatment for neuropsychiatric disorders.},
}

@article {pmid40929163,
year = {2025},
author = {Schwertner, K and Basílio, J and Hoffmann-Sommergruber, K and Ellinger, I and Geiselhart, S},
title = {Global transcriptional analysis of human FHs 74 Int intestinal epithelial cells after exposure to advanced glycation end products.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0331325},
doi = {10.1371/journal.pone.0331325},
pmid = {40929163},
issn = {1932-6203},
mesh = {Humans ; *Glycation End Products, Advanced/pharmacology ; *Intestinal Mucosa/metabolism/cytology/drug effects ; *Epithelial Cells/metabolism/drug effects ; S100A12 Protein/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; Cell Line ; Gene Expression Regulation/drug effects ; Cell Proliferation/drug effects ; },
abstract = {Advanced glycation end products (AGEs) and reactive intermediates, such as methylglyoxal, are formed during thermal processing of foods and have been implicated in the pathogenesis of a series of chronic inflammatory diseases. AGEs are thought to directly interact with the intestinal epithelium upon ingestion of thermally processed foods, but their effects on intestinal epithelial cells are poorly understood. This study investigated transcriptomic changes in human intestinal epithelial FHs 74 Int cells after exposure to AGE-modified human serum proteins (AGE-HS), S100A12, a known RAGE ligand, and unmodified human serum proteins (HS). In contrast to previous studies employing cancer cell lines, RNA sequencing of FHs 74 Int cells treated with AGE-HS did not reveal transcriptional changes associated with increased proliferation, increased expression of tight junction proteins or proinflammatory responses. Surprisingly, neither AGE-HS nor S100A12 treatments resulted in significant differential gene expression at standard analysis thresholds, while unmodified HS induced minor transcriptional changes. Gene set enrichment analysis revealed that AGE-HS treatment induced downregulation of gene sets linked to MYC, interferon responses, and oxidative phosphorylation, as well as pathways related to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, paralleling some effects observed with S100A12. This is the first global transcriptomic analysis of FHs 74 Int cells and the first unbiased investigation of signaling pathway alterations in intestinal epithelial cells exposed to AGEs. In contrast to previous studies, this analysis did not reveal any significantly differentially expressed genes, thus challenging previous reports of robust AGE-induced inflammatory and proliferative effects and emphasizing the importance of an isolated experimental setting and rigorous endotoxin testing.},
}

Humans
*Glycation End Products, Advanced/pharmacology
*Intestinal Mucosa/metabolism/cytology/drug effects
*Epithelial Cells/metabolism/drug effects
S100A12 Protein/pharmacology
*Transcriptome/drug effects
Gene Expression Profiling
Cell Line
Gene Expression Regulation/drug effects
Cell Proliferation/drug effects

@article {pmid40928812,
year = {2025},
author = {Taragano, F and Seinhart, D and Epstein, P and Sylvestre, V and Barañano, C and Otero Castro, V and Sánchez, V and Kilstein, A and González, R and Franco-Trecu, V and Costa-Urrutia, P},
title = {A real-world study on the safety and efficacy of therapeutic plasma exchange in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375430},
doi = {10.1177/13872877251375430},
pmid = {40928812},
issn = {1875-8908},
abstract = {BackgroundTherapeutic plasma exchange (TPE) with albumin replacement has emerged as a potential treatment for Alzheimer's disease (AD). The AMBAR trial showed that TPE could slow cognitive and functional decline, along with changes in core and inflammatory biomarkers in cerebrospinal fluid.ObjectiveTo evaluate the safety and effectiveness of TPE in a real-world setting in Argentina.MethodsFrom 2022 to 2024, 32 patients with mild-to-moderate AD received TPE and were compared to a historical control group (2008-2018, n = 194) matched for inclusion criteria and cognitive assessments. The protocol included six weekly intensive sessions followed by at least 10 monthly maintenance sessions. Outcomes were measured using the Mini-Mental State Examination (MMSE), and tests of memory, language, executive function, and attention. Linear models were used for analysis.ResultsPatients had a mean age of 72.1 years; 42.4% were female. Baseline MMSE scores ranged from 15 to 26. A total of 514 procedures were performed; 81.5% were uneventful. Mild-to-moderate adverse events occurred in 18.5% of sessions, mainly related to venipuncture; no severe events were reported. Mean plasma exchange volumes were 88.2% and 49.8% of estimated plasma volume during the intensive and maintenance phases, respectively. TPE significantly slowed MMSE decline (45% less than controls, p < 0.001) and reduced memory deterioration (88% less in immediate recall, p < 0.001; 74% in delayed recall, p = 0.04). Other domains were also better preserved.ConclusionsTPE appears to be a safe and effective intervention for slowing cognitive decline in AD, supporting the AMBAR findings.},
}

@article {pmid40928277,
year = {2025},
author = {Fu, JX and Wang, WP and Wang, YD and Wang, PC},
title = {Beams of Hope: Shedding New Light on Alzheimer's Treatment with Low-Dose Radiation Therapy.},
journal = {Biomedical and environmental sciences : BES},
volume = {38},
number = {8},
pages = {1001-1002},
doi = {10.3967/bes2025.100},
pmid = {40928277},
issn = {2214-0190},
}

@article {pmid40928009,
year = {2025},
author = {Weden, MM and Frank, L and Dick, AW and Wang, Z and Peschin, S and Bovenkamp, DE and Rossi, SL and Sciullo, D and Hillerstrom, H and Fisher, RA},
title = {Investment in Alzheimer's disease research for the next generation of adults with Down syndrome will yield health benefits for future generations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70348},
doi = {10.1002/alz.70348},
pmid = {40928009},
issn = {1552-5279},
support = {//LuMind IDSC Foundation/ ; //Alliance for Aging Research/ ; //BrightFocus® Foundation/ ; //National Down Syndrome Society/ ; },
mesh = {Humans ; *Down Syndrome/economics/complications/epidemiology/therapy ; *Alzheimer Disease/economics/therapy/epidemiology ; Life Expectancy ; Adult ; *Biomedical Research/economics ; Caregivers/economics ; },
abstract = {Recent innovations in Alzheimer's disease (AD) treatment highlight critical gaps in knowledge about how to support healthy aging of adults with Down syndrome (DS). RAND researchers updated demographic and epidemiological evidence about the DS population to assess the impact of increased investment in treatment innovations for DS-associated Alzheimer's disease (DS-AD). They estimated life expectancy at birth in 2020 to be 55 years, with ≈ 5 years of DS-AD. They found that the results of investment were dramatic. Between 2020 and 2070, adult years of life are expected to increase by 5 years without any increase in unhealthy years of life with DS-AD. Caregiving hours for individuals with DS-AD are expected to be reduced by 40%, which will generate large annual savings. The new evidence underscores the magnitude of the impact that investment in DS-AD treatments could have for individuals with DS, their families, and caregivers. HIGHLIGHTS: Evidence is sparse about treatment for Down syndrome (DS)-associated Alzheimer's disease (DS-AD) and healthy aging of DS adults. This population simulation model estimates DS-AD caregiving costs at ≈ $1 billion per year. DS-AD innovations could increase life expectancy by 5 years and reduce caregiving by 40% by 2070. This better forecasting can improve policy and service planning. DS-AD research investment could yield dramatic gains for individuals and families.},
}

Humans
*Down Syndrome/economics/complications/epidemiology/therapy
*Alzheimer Disease/economics/therapy/epidemiology
Life Expectancy
Adult
*Biomedical Research/economics
Caregivers/economics

@article {pmid40927759,
year = {2025},
author = {Aggarwal, A and Rajalekshmi, R and Aggarwal, A and Agrawal, DK},
title = {Plants, Pills, and the Brain: Exploring Phytochemicals and Neurological Medicines.},
journal = {International journal of plant, animal and environmental sciences},
volume = {15},
number = {3},
pages = {90-114},
pmid = {40927759},
issn = {2231-4490},
abstract = {Neurological disorders, such as Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injuries, and traumatic brain injuries, represent substantial global health challenges due to their chronic and often progressive nature. While allopathic medicine offers a range of pharmacological interventions aimed at managing symptoms and mitigating disease progression, it is accompanied by limitations, including adverse side effects, the development of drug resistance, and incomplete efficacy. In parallel, phytochemicals-bioactive compounds derived from plants-are receiving increased attention for their potential neuroprotective, antioxidant, and anti-inflammatory properties. This review will explore the therapeutic landscape of neurological diseases by providing a comprehensive overview of prevalent conditions and the current allopathic treatments available. Furthermore, this review will investigate specific phytochemicals, including flavonoids, alkaloids, and terpenoids, that exhibit promise in modulating various disease pathways. Emphasis will be placed on the interactions between plant-derived compounds and prescription medications, highlighting both potential synergistic effects and possible adverse interactions. A thorough understanding of these interactions is essential for the development of integrative treatment approaches that enhance therapeutic efficacy while minimizing harm. By bridging traditional herbal medicine with contemporary pharmacotherapy, this review aims to promote a more holistic perspective on the management of neurological diseases, while also encouraging further research into safe and effective combinatory therapies.},
}

@article {pmid40927393,
year = {2025},
author = {Ning, G and Fan, X and Juan, D and Wenxue, Z and Sijia, W and Meinei, C and Xiaolong, D and Yiming, Q},
title = {The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1637671},
pmid = {40927393},
issn = {1663-4365},
abstract = {The intramembrane aspartic protease, γ-secretase, is a heterotetrameric protein complex composed of four integral membrane proteins: presenilin (PSEN), nicastrin (NCT), Anterior pharynx defective-1 (APH-1), and presenilin enhancer 2 (PEN-2). These components are sequentially assembled into a functional complex. γ-secretase is ubiquitously expressed in all cells and tissues and exhibits enzymatic activity akin to "molecular scissors" by cleaving various type I transmembrane proteins. The primary substrates of this complex include amyloid precursor protein (APP) and Notch. The role of APP in the pathogenesis of Alzheimer's disease (AD) has been extensively investigated. Although γ-secretase inhibitors (GSIs) have been evaluated for their therapeutic potential in AD, their clinical application is limited due to significant toxic side effects. Recently, γ-secretase modulators (GSMs) have emerged as promising alternatives, offering new opportunities for the treatment of AD, especially the inherent γ-secretase modulatory proteins (GSMPs) within cells. Research on GSMPs has ushered in a new era for mitigating the side effects of AD drugs. In this review, we systematically summarize recent advancements in the study of γ-secretase in relation to AD and provide an overview of GSMs and GSMPs, thereby offering potential insights for the development of therapeutic strategies for AD.},
}

@article {pmid40927301,
year = {2025},
author = {Heller, LI and Lowe, AS and Del Rosario Hernández, T and Gore, SV and Chatterjee, M and Creton, R},
title = {Target the Heart: A New Axis of Alzheimer's Disease Prevention.},
journal = {Journal of dementia and alzheimer's disease},
volume = {2},
number = {2},
pages = {},
pmid = {40927301},
issn = {3042-4518},
abstract = {BACKGROUND/OBJECTIVE: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer's disease.

METHODS: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin.

RESULTS: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin-NFAT pathway, like cyclo-sporine A, providing a potential mechanism.

CONCLUSIONS: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer's disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration.},
}

@article {pmid40926822,
year = {2025},
author = {Guo, W and Dong, L and Lu, Q and Xie, M and Yang, Y and Zhang, Y and Lu, X and Yu, Q},
title = {Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.},
journal = {Alpha psychiatry},
volume = {26},
number = {4},
pages = {46108},
pmid = {40926822},
issn = {2757-8038},
abstract = {BACKGROUND: The progressive legalization and widespread use of cannabis has led to its use as a treatment for certain neuropsychiatric disorders. Traditional epidemiological studies suggest that cannabis use has an effect on some neurocognitive aspects. However, it is unclear whether cannabis use is causally related to common neuropsychiatric disorders. The present study was conducted to illustrate the causal relationships of genetically predicted cannabis use with common neuropsychiatric disorders.

METHODS: We used a two-sample Mendelian randomization method using genome-wide association study (GWAS) summary statistics obtained from publicly available databases on lifetime cannabis use and 10 neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), epilepsy, generalized epilepsy, focal epilepsy, migraine, migraine with aura, migraine without aura, schizophrenia (SCZ), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and Parkinson's disease (PD) were studied with a two-sample Mendelian randomization method for GWAS summary statistics. The inverse variance weighted (IVW) method was used as the main analysis model.

RESULTS: Our study suggests that lifetime cannabis use is associated with an increased risk of developing PD (odds ratio (OR) = 1.782; 95% CI 1.032-3.075; p = 0.038) and an increased risk of ADHD in female participants (OR = 1.650; 95% CI 1.051-2.590; p = 0.029).

CONCLUSIONS: Cannabis intake may cause adverse effects relating to certain neuropsychiatric disorders. Therefore, special attention should be paid to the side effects of addictive drugs during clinical treatment to avoid harmful effects on the brain and neurocognition.},
}

@article {pmid40926795,
year = {2025},
author = {Zhang, Y and Silang, Q and Wang, Y and Wang, N and Gesang, L and Tang, L and Liu, L},
title = {Integrated Gut Microbiota, Metabolomics, and Network Pharmacology to Investigate the Anti-Alzheimer's Mechanism of Tripterygium Glycoside.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {1911-1933},
pmid = {40926795},
issn = {1176-6328},
abstract = {BACKGROUND: Tripterygium glycoside (TG) has been reported to have the effect of ameliorating Alzheimer's disease (AD)-like symptoms in mice model. However, the underlying mechanism is largely unknown. This study aimed to investigate the potential mechanism of TG against AD by integrating metabolomics, 16s rRNA sequencing, network pharmacology, molecular docking, and molecular dynamics simulation.

METHODS: Memory and cognitive functions were assessed in mice via the Morris water maze. The pathological changes were assessed using hematoxylin and Nissl's straining. Pathological changes in p-Tau and Aβ1-42 were assessed using immunohistochemistry, immunofluorescence, ELISA, and Western blotting. 16S rRNA sequencing and metabolomics were performed to analyze alterations in the structure of gut microbiota and hippocampus metabolites. Network pharmacology, molecular docking, and molecular dynamics simulation were performed to determine the putative molecular regulatory mechanism of TG in treating AD.

RESULTS: TG significantly could inhibit neuron loss, improved cognitive and memory functions, and significantly reduce the expression of p-Tau and Aβ1-42. In addition, 16s rRNA analysis revealed that TG could reverse AD-induced gut microbiota dysbiosis in AD model mice by reducing the abundance of Alistipes. Furthermore, metabolomic analysis revealed that TG may reverse AD-induced metabolic disorders by regulating glycerophospholipid metabolism. And spearman analysis revealed that glycerophospholipids metabolism might closely related to Alistipes. Moreover, network pharmacology, molecular docking, and molecular dynamics simulation analyses indicated that TG might regulate lipid metabolism-related pathways via SRC for the treatment of AD.

CONCLUSION: TG may serve as a potential therapeutic drug for preventing AD via the microbiota-gut-brain axis.},
}

@article {pmid40926603,
year = {2025},
author = {Porwal, S and Malviya, R and Sridhar, SB and Wadhwa, T and Shareef, J and Meenakshi, DU},
title = {Trends and Advancements in Smart Electrospun Food Fibers for the Management of Neurological Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273375873250829060106},
pmid = {40926603},
issn = {1996-3181},
abstract = {Neurological disorders are complex conditions characterized by impairment of the nervous system, affecting motor, cognitive, and sensory functions. Current treatments meet substantial obstacles, primarily due to the difficulty of transporting drugs across the blood-brain barrier and ineffective therapy for nerve regeneration. Emerging technologies, such as electrospinning, offer innovative solutions to overcome these challenges. The study explores the potential of electrospun food fibers in managing and treating neurological disorders, concentrating on their role in drug delivery and nerve tissue regeneration. Electrospinning allows for the generation of nanofibers from diverse natural and synthetic polymers that imitate the extracellular matrix and stimulate brain healing. These fibers may be loaded with therapeutic drugs, permitting controlled, localized drug release while limiting systemic toxicity. For instance, electrospun fibers loaded with neuroprotective drugs, such as donepezil and levodopa, have exhibited better drug stability, enhanced bioavailability, and prolonged therapeutic efficacy in treating syndromes such as Alzheimer's and Parkinson's diseases. Furthermore, the biodegradable and biocompatible nature of food-based polymers like chitosan, cellulose, and zein makes them great candidates for medicinal applications, minimizing the risk of inflammation and unfavorable immunological reactions. In conclusion, electrospun food fibers show tremendous promise in resolving the issues of drug delivery and nerve regeneration in neurological illnesses. Their capacity to boost therapeutic results via targeted and regulated drug release makes them a possible alternative to established treatment procedures, bringing renewed hope to patients suffering from neurodegenerative disorders.},
}

@article {pmid40926398,
year = {2025},
author = {Nie, RZ and Zhang, QL and Tan, XR and Hu, SS and Zhou, XT and Jiang, WK and Guo, BW and Cao, X and Yuan, DH and Long, Y and Hong, H and Tang, SS},
title = {Cholinergic G protein-coupled bile acid receptor 1 (TGR5/GPBA) in the medial septal orchestrates adult hippocampal neurogenesis and cognition in Alzheimer's disease mice.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70185},
pmid = {40926398},
issn = {1476-5381},
support = {82071202//National Natural Science Foundation of China/ ; 82173805//National Natural Science Foundation of China/ ; 82373860//National Natural Science Foundation of China/ ; 2024YFA1308200//National Key Research and Development Program of China/ ; },
abstract = {BACKGROUND AND PURPOSE: The pathological role of the bile acid receptor TGR5/GPBA in Alzheimer's disease (AD) is not fully understood. We investigated the pharmacological effects and mechanisms of TGR5 in AD model mice.

EXPERIMENTAL APPROACH: TGR5 expression was assessed in AD mice using immunofluorescence and immunoblotting. Bidirectional modulation of TGR5 expression was achieved via stereotaxic delivery of adeno-associated virus vectors, while localized pharmacological activation was conducted through intracerebral cannula implantation. Cognition was evaluated using the Morris water maze and novel object recognition test. Adult hippocampal neurogenesis was assessed via immunofluorescence. Neuronal activity was analysed using immunofluorescence, fibre photometry and chemogenetics-coupled fibre photometry. Acetylcholine dynamics were monitored using fibre photometry, both alone and in combination with chemogenetic manipulation.

KEY RESULTS: TGR5 expression was selectively decreased in the medial septal (MS) cholinergic neurons during middle-late AD stages. Bidirectional genetic regulation of TGR5 in MS cholinergic neurons significantly affected cognition and adult hippocampal neurogenesis in mice. Pharmacological activation of TGR5 in the MS not only increased cholinergic neuronal activity and acetylcholine release, but also enhanced DG glutamatergic neuronal activity, acetylcholine levels and neurogenesis in AD mice. TGR5 modulated cognition and neurogenesis via the MS[cholinergic(ChAT)]→ DG[glutamatergic(Glu)] circuit. Furthermore, α7 nAChRs in the DG were involved in TGR5-mediated improvements in cognition and neurogenesis.

CONCLUSION AND IMPLICATIONS: Our findings demonstrate that TGR5 in MS cholinergic neurons is critical during the middle-late stage of AD and provide valuable insights into the underlying neuronal circuit mechanisms. TGR5 (GPBA) represents a potential therapeutic target for AD treatment.},
}

@article {pmid40925485,
year = {2025},
author = {Prokop-Millar, S and Di Passa, AM and Yaya, H and McIntyre-Wood, C and Farzan, F and Terpstra, A and Fein, A and Vandehei, E and MacKillop, E and MacKillop, J and Duarte, D},
title = {Predictive and mechanistic biomarkers of treatment response to Transcranial Magnetic Stimulation (TMS) in Psychiatric and Neurocognitive Disorders, identified via TMS-Electroencephalography (EEG) and Resting-State EEG: A systematic review.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120194},
doi = {10.1016/j.jad.2025.120194},
pmid = {40925485},
issn = {1573-2517},
abstract = {Electroencephalography (EEG) is a comparatively inexpensive and non-invasive recording technique of neural activity, making it a valuable tool for biomarker discovery in transcranial magnetic stimulation (TMS). This systematic review aimed to examine mechanistic and predictive biomarkers, identified through TMS-EEG or resting-state EEG, of treatment response to TMS in psychiatric and neurocognitive disorders. Nineteen articles were obtained via Embase, APA PsycInfo, MEDLINE, and manual search; conditions included, unipolar depression (k = 13), Alzheimer's disease (k = 3), bipolar depression (k = 2), and schizophrenia (k = 2). Two mechanistic biomarkers were identified: one TMS-EEG marker, reductions in N100 post-dorsolateral prefrontal cortex (DLPFC) repetitive TMS or intermittent theta burst stimulation (iTBS) in unipolar depression (n = 120; k = 2), and one resting-state marker, reductions in theta connectivity post-DLPFC repetitive TMS in unipolar and bipolar depression (n = 89; k = 2). Whereas one predictive TMS-EEG biomarker was isolated: greater baseline N100 was predictive of unipolar depression improvement in DLPFC repetitive TMS and iTBS (n = 113; k = 2). Promising markers were briefly discussed for future research in Alzheimer's disease and schizophrenia. In conclusion, across the psychiatric and neurocognitive disorders considered in this study, TMS-EEG and resting-state mechanistic and predictive biomarkers of depression appear to hold the most promise. Further research is needed to validate the biomarkers identified in depression, to help guide treatment plans and advance precision medicine in psychiatry.},
}

@article {pmid40925435,
year = {2025},
author = {Liu, Y and Wang, Y and Liang, Y and Yang, S and Deng, Y and Zeng, S and Wang, Y and Shu, Z and Shuai, Y and Guo, H},
title = {Transcriptomics and metabolomics revealed the effects of Polygonatum Rhizoma polysaccharide on delaying C. elegans senescence and ameliorating Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {147375},
doi = {10.1016/j.ijbiomac.2025.147375},
pmid = {40925435},
issn = {1879-0003},
abstract = {We explored the role of Polygonatum Rhizoma polysaccharide (PRP) in delaying aging and improving Alzheimer's disease (AD) and revealed its potential molecular mechanism. Through chemical characterizations to clarify the physicochemical properties of PRP, it was found that PRP mainly consists of mannose, glucose, galactose, and arabinose, with molecular weights ranging from 7.4 × 10[4] to 9.1 × 10[4] Da; using Caenorhabditis elegans (C. elegans) models, its anti-AD activity was verified by combining approaches using pharmacodynamics, molecular biology, metabolomics, and transcriptomics sequencing. The results of this study showed that PRP significantly extended the lifespan of C. elegans, reduced the accumulations of lipofuscin and increased the ability of C. elegans to resist oxidative stress, and reduced the aggregation of Aβ protein in the AD model C. elegans, and improved neuromuscular dysfunction. Transcriptomic analysis revealed that PRP modulated the expression of genes involved in key processes, including anti-stress and senescence (daf-12, skn-1, gst-4, ctl-1, sod-3, age-1, gcs-1), autophagy (unc-51, bec-1, lgg-1), and mitochondrial function (clk-1, mev-1, isp-1). Metabolomic analysis revealed that PRP improved metabolic disorders in C. elegans by regulating phenylalanine/purine metabolism pathway. These results indicated that PRP exerted its effects through multiple pathways to delay C. elegans aging and improve AD symptoms, providing a strong theoretical basis for the development of AD treatment drugs based on traditional Chinese medicine.},
}

@article {pmid40924554,
year = {2025},
author = {Zhao, ZQ and Liang, L and Hu, LF and He, YT and Jing, LY and Liu, Y and Chen, BZ and Guo, XD},
title = {Correction to "Subcutaneous Implantable Microneedle System for the Treatment of Alzheimer's Disease by Delivering Donepezil".},
journal = {Biomacromolecules},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biomac.5c01588},
pmid = {40924554},
issn = {1526-4602},
}

@article {pmid40923675,
year = {2025},
author = {Evans, RC and Dar, NJ and Chen, L and Na, R and O'Connor, JC and Jiang, J and Zheng, S and Ran, Q},
title = {Inhibition of Hippo Signaling Through Ablation of Lats1 and Lats2 Protects Against Cognitive Decline in 5xFAD Mice via Increasing Neuronal Resilience Against Ferroptosis.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70218},
doi = {10.1111/acel.70218},
pmid = {40923675},
issn = {1474-9726},
support = {R01AG086496/AG/NIA NIH HHS/United States ; R01AG064078/AG/NIA NIH HHS/United States ; I01 BX003507/BX/BLRD VA/United States ; },
abstract = {The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional neuronal ablation of Lats1 and Lats2, the gatekeepers of Hippo signaling activity. Our results indicated that 5xFAD mice with ablation of Lats1 and Lats2 were protected against cognitive decline compared with control 5xFAD mice, and this protection was correlated with a marked reduction in neurodegeneration. Interestingly, primary culture neurons with ablation of Lats1 and Lats2 had significantly increased survival following treatment with chemical inducers of ferroptosis and exhibited reduced lipid peroxidation, the driving force of ferroptotic cell death. Moreover, 5xFAD mice with ablation of Lats1 and Lats2 showed reduced lipid peroxidation, and transcriptomic analysis revealed that 5xFAD mice with ablation of Lats1 and Lats2 had enriched metabolic pathways associated with ferroptosis. These results indicate that inhibition of Hippo signaling activity confers neural protection in 5xFAD mice by augmenting resilience against ferroptosis.},
}

@article {pmid40923656,
year = {2025},
author = {Li, Q and He, B and Xiong, Y},
title = {Calycosin attenuates neuronal ferroptosis in Alzheimer's disease mice by activating the Nrf2/HO-1 pathway.},
journal = {General physiology and biophysics},
volume = {44},
number = {5},
pages = {363-375},
doi = {10.4149/gpb_2025021},
pmid = {40923656},
issn = {0231-5882},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; Mice ; *Neurons/drug effects/metabolism/pathology ; *Isoflavones/pharmacology/administration & dosage ; *Heme Oxygenase-1/metabolism ; Signal Transduction/drug effects ; Male ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Membrane Proteins ; },
abstract = {In this study, we investigated the therapeutic potential of calycosin (from Astragalus) in Alzheimer's disease (AD), focusing on ferroptosis modulation. APP/PS1 mice received 40 mg/kg calycosin for 3 months. Cognitive function was assessed via Morris water maze test. Tau hyperphosphorylation and amyloid-β (Aβ) aggregation were analyzed using immunofluorescence and Western blotting. In vitro, Aβ1-42-treated HT22 neuronal cells were exposed to calycosin. Ferroptosis-related phenotypes were assessed in vivo and in vitro using Prussian blue staining, commercial kits, and Western blotting. The nuclear factor-erythroid factor 2-related factor 2 (Nrf2) signaling was examined by Western blotting. Calycosin treatment significantly improved cognitive deficits in APP/PS1 mice and inhibited Tau hyperphosphorylation and Aβ aggregation. Calycosin attenuated neurotoxicity and Tau hyperphosphorylation in Aβ1-42-treated HT22 cells. Moreover, calycosin inhibited ferroptosis in vivo and in vitro by decreasing iron aggregation and lipid peroxidation, downregulating transferrin receptor expression, and upregulating ferroportin, cystine/glutamate antiporter, and glutathione peroxidase 4 expression. Mechanistically, the anti-ferroptosis effects of calycosin were linked to the activation of the Nrf2-mediated pathway. These findings suggest that calycosin may exhibit neuroprotective effects against neuronal ferroptosis in AD, indicating its potential as a therapeutic candidate for further investigation in AD.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*Ferroptosis/drug effects
*NF-E2-Related Factor 2/metabolism
Mice
*Neurons/drug effects/metabolism/pathology
*Isoflavones/pharmacology/administration & dosage
*Heme Oxygenase-1/metabolism
Signal Transduction/drug effects
Male
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Membrane Proteins

@article {pmid40922888,
year = {2025},
author = {Kademani, A and Avraam, C and Montenegro, D and Paloh, A and Somannagari, N and Gupta, A and Lafi, AW and Algaba, AE and Islam, R and Fahima, C and Siddiqui, HF},
title = {Exploring the Emerging Role of Stem Cell Therapy in Neurodegenerative Diseases and Spinal Cord Injury: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e89629},
pmid = {40922888},
issn = {2168-8184},
abstract = {Neurodegenerative diseases and spinal cord injuries (SCI) pose a significant burden on the healthcare system globally. Diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease precipitate cognitive, motor, and behavioral deficits. Parallelly, spinal cord injuries produce sensory and motor deficits, which are burdensome psychologically, socially, and economically. Current management strategies focus only on symptomatic relief, with no definitive cure. Stem cells have been explored for regenerative therapy. This review focuses on developments, limitations, and future potential of stem cell therapy. Stem cells affect the central nervous system via neuroprotective mechanisms, immunomodulatory effects, and mitigation of oxidative stress. The clinical implications of stem cell therapy in treating neurodegenerative diseases and SCI are debatable due to varied outcomes. Challenges related to sample size, long-term follow-up, and assessment of adverse effects should be mitigated in future research. Researchers are currently exploring optimal stem cell types along with various transplantation strategies. Biomaterials integrated with stem cells are a novel approach for treating neurodegenerative diseases and spinal cord injuries. Certain genetic modifications have shown improved results. Screening patients to ascertain better responses to therapy has proven to be a challenge. Other complications include graft vs. host reaction and degeneration of transplanted neurons due to pathogenesis and tumorigenesis. However, the majority of the potential stem cell therapeutic avenues are in the preclinical stage and are being tested on animal models. Guidelines pertaining to ethical concerns and regulatory frameworks need to be established to unfold the full potential of stem cell therapy in the clinical setting. Recent advances also show an increased need to formulate patient-specific approaches to treatment, ranging from stem cell selection to the technique of transplantation. Ongoing clinical trials can address the current challenges and leverage emerging technologies, leading to definitive treatments for neurodegenerative diseases and spinal cord injuries.},
}

@article {pmid40922863,
year = {2025},
author = {Murali, A and Muddappa, SC and Rajan, RR and Joseph, A and Ravi, AB},
title = {Barriers to Geriatric Oral Health: A Multifaceted Public Health Issue.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e89604},
pmid = {40922863},
issn = {2168-8184},
abstract = {Oral health is important for the overall health of an individual, particularly older adults. However, a number of obstacles frequently prevent older people from receiving timely and appropriate dental care. These obstacles are intricate and multifaceted, involving systemic diseases, cognitive elements, and psychological, financial, and educational issues. Dementia and Alzheimer's disease are examples of cognitive impairments that can make it difficult for an elderly person to seek or cooperate with dental treatment. Additional psychological factors that decrease care-seeking behaviour include anxiety, fear of dental treatments, depression, and a general lack of motivation. Financial constraints are major deterrents, such as low income and no dental insurance. Furthermore, polypharmacy and multimorbidity not only make treatment planning more difficult, but they also deprive oral health of priority. The problem is made worse by systemic healthcare barriers like inadequate referral systems, a lack of geriatric-focused dentists, and poor integration between dental and medical services. Neglect is also exacerbated by older adults' and their caregivers' perceived lack of need for dental care. A comprehensive, multidisciplinary strategy is needed to address these issues, one that incorporates training dental professionals in geriatric care, better public health regulations, caregiver education, and the creation of easily accessible, reasonably priced services. Improving the general and oral health of the elderly requires an understanding of and commitment to removing these obstacles.},
}

@article {pmid40922111,
year = {2025},
author = {Vitali, F and Torrandell-Haro, G and Arias, JC and French, SR and Zahra, S and Brinton, RD and Weinkauf, C},
title = {Carotid endarterectomy mitigates Alzheimer's disease and non-Alzheimer's disease dementia risk linked to asymptomatic carotid stenosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70674},
doi = {10.1002/alz.70674},
pmid = {40922111},
issn = {1552-5279},
support = {R01AG070987/AG/NIA NIH HHS/United States ; R01AG057931/AG/NIA NIH HHS/United States ; P01AG026572/AG/NIA NIH HHS/United States ; //Arizona Alzheimer's Consortium/ ; CTR056056//Arizona Biomedical Research Commission/ ; //Richard and Jan Highberger Award/ ; //Health Sciences, University of Arizona/ ; /DDCF/Doris Duke Charitable Foundation/United States ; },
mesh = {Humans ; *Endarterectomy, Carotid/statistics & numerical data ; *Alzheimer Disease/epidemiology/prevention & control ; *Carotid Stenosis/surgery/complications/epidemiology ; Male ; Female ; Aged ; Retrospective Studies ; Propensity Score ; United States/epidemiology ; Stents ; *Dementia/epidemiology/prevention & control ; Risk Factors ; Incidence ; Middle Aged ; },
abstract = {INTRODUCTION: Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. aECAD treatment includes carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stroke prevention, but their impact on dementia incidence is poorly studied.

METHODS: Propensity score matching was used in a retrospective cohort study of United States-based insurance claims (2010-2022) in 487,676 patients with aECAD to evaluate the effect of CEA and CAS on AD and non-AD dementia incidence.

RESULTS: After matching, 37,317 patients underwent CEA or CAS. CEA was associated with a significantly lower AD risk (relative risk = 0.93; 95% confidence interval, 0.86-0.99; P < 0.05), whereas CAS was associated with a slight but non-significant increase. Similar trends were observed for non-AD dementia.

DISCUSSION: CEA, but not CAS, may confer a protective effect against AD and non-AD dementia in patients with aECAD, a common cerebrovascular disease affecting up to 15% of adults over age 60.

HIGHLIGHTS: Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. Limited studies have evaluated the role of carotid endarterectomy (CEA) and (carotid artery stenting (CAS) on dementia outcomes. Using United States-based insurance claims data, 487,676 patients with aECAD were evaluated. After propensity score matching, CEA was significantly associated with reduced AD risk. CAS was not significantly associated with a change in AD risk.},
}

Humans
*Endarterectomy, Carotid/statistics & numerical data
*Alzheimer Disease/epidemiology/prevention & control
*Carotid Stenosis/surgery/complications/epidemiology
Male
Female
Aged
Retrospective Studies
Propensity Score
United States/epidemiology
Stents
*Dementia/epidemiology/prevention & control
Risk Factors
Incidence
Middle Aged

@article {pmid40922100,
year = {2025},
author = {Floud, S and Hermon, C and Whiteley, W and Fitzpatrick, KE and Reeves, GK},
title = {Hypertension in pregnancy and in midlife and the risk of dementia: prospective study of 1.3 million UK women.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70595},
doi = {10.1002/alz.70595},
pmid = {40922100},
issn = {1552-5279},
support = {A29186/CRUK_/Cancer Research UK/United Kingdom ; CAF/17/01//Chief Scientist's Office/ ; //Health Data Research UK/ ; //BHD Data Science Centre/ ; /ALZS_/Alzheimer's Society/United Kingdom ; CAF/17/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; },
mesh = {Humans ; Female ; Pregnancy ; *Dementia/epidemiology ; United Kingdom/epidemiology ; Prospective Studies ; Middle Aged ; Risk Factors ; *Hypertension/epidemiology/complications ; Adult ; *Hypertension, Pregnancy-Induced/epidemiology ; Aged ; Proportional Hazards Models ; Dementia, Vascular/epidemiology ; },
abstract = {INTRODUCTION: Midlife hypertension is associated with dementia risk, although uncertainties remain regarding its association with subtypes and regarding the effect of pregnancy-related hypertension on dementia risk.

METHODS: In the Million Women Study, 1,363,457 women (mean age 57) were asked about current treatment for hypertension and hypertension in pregnancy and were followed for first hospital record with any mention of dementia. Cox regression yielded hazard ratios (HRs) adjusted for socioeconomic, lifestyle, and metabolic factors.

RESULTS: With 84,729 dementia cases over 21 years, midlife hypertension was positively associated with dementia (HR 1.17, 95% confidence interval [CI] 1.15 to 1.19); higher for vascular dementia (VaD) (HR 1.50; 95% CI 1.45 to 1.56) than Alzheimer's disease (AD) (HR 1.01; 95% CI 0.98 to 1.04). Hypertension in pregnancy but not in midlife was only weakly associated with dementia (HR 1.04; 95% CI 1.01 to 1.06).

DISCUSSION: Midlife hypertension is a strong risk factor for dementia, largely through VaD. Hypertension during pregnancy does not appear to materially affect dementia risk.

HIGHLIGHTS: Midlife hypertension was associated with long-term all-cause dementia risk. Midlife hypertension was associated with VaD, not AD. Hypertension in pregnancy has little effect on dementia risk.},
}

Humans
Female
Pregnancy
*Dementia/epidemiology
United Kingdom/epidemiology
Prospective Studies
Middle Aged
Risk Factors
*Hypertension/epidemiology/complications
Adult
*Hypertension, Pregnancy-Induced/epidemiology
Aged
Proportional Hazards Models
Dementia, Vascular/epidemiology

@article {pmid40922096,
year = {2025},
author = {Ottoy, J and Owsicki, N and Bilgel, M and Binette, AP and Salvadó, G and Kang, MS and Cash, DM and Ewers, M and La Joie, R and Wisse, LEM and Goubran, M and Betthauser, T},
title = {Recent advances in neuroimaging of Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70648},
doi = {10.1002/alz.70648},
pmid = {40922096},
issn = {1552-5279},
support = {CIHR-PJT-190220//Canadian Institutes for Health Research/ ; CIHR-187890//Canadian Institutes for Health Research/ ; ALZ23-05//Alzheimer Society of Canada/ ; ALZ26-021//Alzheimer Society of Canada/ ; 24AARF-1242638/ALZ/Alzheimer's Association/United States ; 22AARF-972612/ALZ/Alzheimer's Association/United States ; SG-666374-UK/ALZ/Alzheimer's Association/United States ; AARG-22-926899/ALZ/Alzheimer's Association/United States ; AS-DRL-23-005//Alzheimer's Society Dementia Research Leaders Fellowship/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; 101061836//European Union's Horizon 2020 Research and Innovation Program/ ; //Strategic Research Area MultiPark/ ; A2024012F//BrightFocus Foundation/ ; A2024007F//BrightFocus Foundation/ ; R01AG080766//National Institutes of Health National Institute on Aging/ ; P30AG062715//National Institutes of Health National Institute on Aging/ ; R01AG027161//National Institutes of Health National Institute on Aging/ ; P30AG062422//National Institutes of Health National Institute on Aging/ ; 24AARF-1242638//Brain Canada/ ; AF-980942//Alzheimerfonden/ ; AF-994514//Alzheimerfonden/ ; AF-1012218//Alzheimerfonden/ ; BMBF//ERAPerMed/ ; 01KU2203//ERAPerMed/ ; //Alzheimer's Society Research Program/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Neuroimaging/methods/trends ; Biomarkers ; *Brain/diagnostic imaging/pathology ; *Dementia/diagnostic imaging ; Positron-Emission Tomography ; Disease Progression ; tau Proteins/metabolism ; },
abstract = {This review covers recent advances (2023-2024) in neuroimaging research into the pathophysiology, progression, and treatment of Alzheimer's disease (AD) and related dementias (ADRD). Despite the rapid emergence of blood-based biomarkers, neuroimaging continues to be a vital area of research in ADRD. Here, we discuss neuroimaging as a powerful tool to topographically visualize and quantify amyloid, tau, neurodegeneration, inflammation, and vascular disease in the brain. We examine the utility of neuroimaging for (1) tracking the spatiotemporal progression of pathology, (2) serving as the reference standard for validating novel fluid biomarkers, (3) characterizing disease heterogeneity, (4) exploring the role of brain networks in ADRD progression, and (5) evaluating biomarkers for better individualized estimates of treatment benefit. Finally, we discuss advances in radiotracer development and AD risk factors. By reviewing the most promising breakthroughs in the neuroimaging field, we hope to spark new ideas for future discoveries that will deepen our understanding of ADRD. HIGHLIGHTS: The diagnostic and staging criteria for Alzheimer's disease (AD) were updated in 2024. Despite robust harmonization methods for amyloid beta positron emission tomography (PET), parallel efforts for tau PET remain challenging. Larger anti-amyloid drug effects were seen at lower levels of amyloid and tau PET. Phosphorylated tau217 (p-tau217) is currently the most promising plasma biomarker to detect AD pathology. There are new tracer developments for alpha-synuclein, primary tauopathies, and inflammation.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Neuroimaging/methods/trends
Biomarkers
*Brain/diagnostic imaging/pathology
*Dementia/diagnostic imaging
Positron-Emission Tomography
Disease Progression
tau Proteins/metabolism

@article {pmid40921933,
year = {2025},
author = {Sehlin, D and Aguilar, X and Cortés-Canteli, M and Syvänen, S and Lopes van den Broek, S},
title = {Brain-penetrating peptide and antibody radioligands for proof-of-concept PET imaging of fibrin in Alzheimer's disease.},
journal = {EJNMMI radiopharmacy and chemistry},
volume = {10},
number = {1},
pages = {59},
pmid = {40921933},
issn = {2365-421X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multifactorial disorder with vascular contributions, including a pro-coagulant state marked by fibrin deposition in the brain. Fibrin accumulation may exacerbate cerebral hypoperfusion and neuroinflammation, leading to neurodegeneration. Identifying patients with this pathology could enable targeted anticoagulant therapy. However, current imaging tools lack the specificity and sensitivity to detect fibrin in the brain non-invasively. This study aimed to develop and evaluate brain-penetrating peptide- and antibody-based PET radioligands targeting fibrin to enable individualized treatment strategies in AD.

RESULTS: A fibrin-binding peptide (FBP) was conjugated to the antibody fragment scFv8D3, which targets the transferrin receptor (TfR), to facilitate transcytosis across the blood-brain barrier. FBP-scFv8D3 bound TfR and with modest affinity to fibrin. In vivo studies in Tg-ArcSwe mice, that exhibit fibrin along with brain amyloid-β pathology, and wild-type mice showed that [[125]I]FBP-scFv8D3 retained brain-penetrating properties but did not demonstrate significant fibrin-specific retention. In contrast, the monoclonal antibody 1101 and its bispecific, brain penetrant variant 1101-scFv8D3 exhibited higher fibrin selectivity and TfR binding. Both antibodies showed a trend towards higher brain retention in Tg-ArcSwe mice and [[125]I]1101-scFv8D3 showed a higher brain-to-blood ratio compared to [[124]I]1101. PET imaging with [[124]I]1101 and [[124]I]1101-scFv8D3 revealed low global brain uptake. However, ex vivo autoradiography and regional PET quantification (ROI-to-cerebellum ratios) indicated significant cortical and caudate retention of [[124]I]1101-scFv8D3 in Tg-ArcSwe mice, supporting region-specific target engagement.

CONCLUSION: This proof-of-concept study demonstrates the feasibility of using bispecific antibody-based PET radioligands to target fibrin in the AD brain. While the FBP-scFv8D3 conjugate showed limited specificity, the bispecific antibody 1101-scFv8D3 exhibited higher brain penetration and fibrin selectivity. These findings support further development of antibody-based imaging tools toward the goal to stratify AD patients who may benefit from anticoagulant therapy.},
}

@article {pmid40921720,
year = {2025},
author = {Moreira, IP and Vieira-Coelho, MA and Guimarães, J},
title = {Dopamine System Dysfunction in Alzheimer's Disease.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {25},
number = {5},
pages = {e70097},
doi = {10.1111/psyg.70097},
pmid = {40921720},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology ; *Dopamine/metabolism ; Animals ; Disease Models, Animal ; Cognitive Dysfunction ; *Receptors, Dopamine/metabolism ; },
abstract = {The dopaminergic system may be at the base of some neurobehavioral symptoms, as apathy and depression, and extrapyramidal symptoms, often seen in Alzheimer's disease patients. It can also have an impact on cognitive decline, as extrapyramidal symptoms, classically linked with dopamine dysfunction, are associated with increased risk of cognitive impairment and Alzheimer's disease progression. We review the knowledge of the dopaminergic system, emphasizing changes in Alzheimer's disease. Both animal models, post-mortem and in vivo human studies, point to a dopaminergic system dysfunction in this disease. Dopamine dysfunction seems more associated with neuronal loss, modification of dopamine receptors and anomalies in terminal function, including irregularities in dopamine metabolism, than with neurofibrillary tangles or β-amyloid plaques depositions. This dysfunction has an impact on both cognitive and non-cognitive symptoms. A better understanding of the dopaminergic system may help in understanding the pathophysiology of Alzheimer's disease and assist in the diagnosis. Clinical trials aimed at modulating the dopaminergic system may be promising in the treatment of symptoms associated with Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism/physiopathology
*Dopamine/metabolism
Animals
Disease Models, Animal
Cognitive Dysfunction
*Receptors, Dopamine/metabolism

@article {pmid40920304,
year = {2025},
author = {Bhujbal, SP and Hah, JM},
title = {Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis.},
journal = {Archives of pharmacal research},
volume = {},
number = {},
pages = {},
pmid = {40920304},
issn = {1976-3786},
support = {NRF-RS-2020-NR049583//National Research Foundation of Korea/ ; NRF- RS-2024-00397929//National Research Foundation of Korea/ ; NRF-RS-2024-00333784//National Research Foundation of Korea/ ; },
abstract = {c-Jun N-terminal kinases (JNKs), a subfamily of mitogen-activated protein kinases (MAPKs), are key mediators of cellular responses to environmental stress, inflammation, and apoptotic signals. The three isoforms-JNK1, JNK2, and JNK3 exhibit both overlapping and isoform-specific functions. While JNK1 and JNK2 are broadly expressed across tissues and regulate immune signaling, cell proliferation, and apoptosis, JNK3 expression is largely restricted to the brain, heart, and testis, where it plays a crucial role in neuronal function and survival. Subtle structural variations among the isoforms, particularly within the ATP-binding pocket and activation loop, provide a basis for the developing isoform-selective inhibitors to improve therapeutic precision. JNK3 has been increasingly recognized for its involvement in the pathogenesis of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, through mechanisms involving neuroinflammation, oxidative stress, and neuronal apoptosis. Given the limited efficacy of current therapies, which remain largely symptomatic and do not modify disease progression, covalent inhibitors of JNK3 represent a compelling alternative due to their potential for high selectivity and sustained target engagement. In parallel, JNK signaling contributes to fibrosis, with JNK1 serving as the predominant isoform driving profibrotic pathways such as fibroblast activation and extracellular matrix (ECM) deposition. Current antifibrotic agents provide only partial benefit and lack specificity for downstream effectors like JNK1. PROteolysis TArgeting Chimeras (PROTACs), which induce selective protein degradation via the ubiquitin-proteasome system, represent a promising modality to overcome these limitations. Selective degradation of JNK1 could provide a novel therapeutic avenue for fibrotic diseases. This review highlights therapeutic efforts to date and discusses how emerging approaches-particularly covalent JNK3 inhibitors for neurodegeneration and PROTACs for JNK1 in fibrosis-may advance future treatment paradigms.},
}

@article {pmid40920073,
year = {2025},
author = {Peng, L and Xie, X and Chen, X and Chen, C},
title = {Electrochemical Biosensors Combined with Nanomaterial Signal Amplification for the Detection of Alzheimer's Disease Biomarkers in Blood.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.5c02453},
pmid = {40920073},
issn = {2379-3694},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline and behavioral impairments, typically manifesting in the elderly and presenile population. With the rapid global aging trend, early diagnosis and treatment of AD have become increasingly urgent research priorities. The primary pathological features of AD include excessive accumulation of β-amyloid (Aβ) plaques, the formation of neurofibrillary tangles, and neuronal loss. Conventional diagnostic techniques, such as positron emission tomography-computed tomography (PET-CT) and cerebrospinal fluid (CSF) analysis, are limited by their high cost and invasiveness. As a result, there is growing interest in developing blood-based biomarker assays for AD detection. Electrochemical biosensors offer notable advantages in this context, including high sensitivity, low cost, and minimally invasive sampling. However, due to the extremely low concentrations of AD-related biomarkers in blood, signal amplification is necessary. The incorporation of nanomaterials significantly enhances the sensitivity and performance of the electrochemical biosensors. This Perspective highlights the application of various nanomaterial-enhanced electrochemical biosensors in the early diagnosis and disease monitoring of AD, underscoring their potential in advancing AD prevention, diagnosis, and therapeutic strategies.},
}

@article {pmid40919318,
year = {2025},
author = {Harrison, D and Billinton, A and Bock, MG and Clarke, NP and Digby, Z and Gabel, CA and Lindsay, N and Reader, V and Scanlon, J and Smolak, P and Thornton, P and Wescott, H and Watt, AP},
title = {Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as an in vivo tool compound for neuroinflammatory disorders.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {40919318},
issn = {2632-8682},
abstract = {Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.},
}

@article {pmid40919134,
year = {2025},
author = {Zheng, K and Huang, HZ and Liu, D and Brazhe, N and Chen, J and Zhu, LQ},
title = {Targeting the miR-96-5p/Cathepsin B Pathway to Alleviate Neuron-Derived Neuroinflammation in Alzheimer's Disease.},
journal = {MedComm},
volume = {6},
number = {9},
pages = {e70368},
pmid = {40919134},
issn = {2688-2663},
abstract = {Alzheimer's disease (AD) is one of the leading causes of dementia in the elderly, and no effective treatment is currently available. Cathepsin B (CTSB) is involved in key pathological processes of AD, but the underlying mechanisms and its relevance to AD diagnosis and treatment remain unclear. In the present study, we found that CTSB expression was abnormally elevated in the hippocampus of 3×Tg mice and was regulated by miR-96-5p. Abnormalities in the miR-96-5p/CTSB signaling pathway were detected in the serum of both mild cognitive impairment and AD patients, and the combination of serum miR-96-5p and CTSB demonstrated strong diagnostic efficacy for cognitive impairment (AUC = 0.7536). Abnormalities in the miR-96-5p/CTSB signaling pathway in AD may be associated with Aβ pathology, and neuronal CTSB can be released extracellularly to reactivate adjacent astrocytes. Ultimately, the reconstitution of the miR-96-5p/CTSB signaling pathway effectively rescued astrocyte reactivity and memory impairment in AD. Our findings suggest that the neuron-derived inflammatory mediator CTSB reactivates adjacent astrocytes and mediates memory impairment in early AD. The combination of serum miR-96-5p and CTSB represents potential serum biomarkers for cognitive impairment, and targeting the neuronal miR-96-5p/CTSB pathway may serve as a promising therapeutic strategy for AD.},
}

@article {pmid40918977,
year = {2025},
author = {Yang, H and Dong, C and Cai, Y and Zhao, M and Liu, J and Bian, S and Ding, X},
title = {Advances in the use of structural and diffusion magnetic resonance imaging for characterizing SCD and MCI due to Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1596459},
pmid = {40918977},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) has become a great concern for society in general and clinicians specifically because of its high morbidity, relative lack of awareness of its characteristics, and low diagnosis and treatment rates. Worldwide, there is a lack of effective treatments for slowing the progression of AD in clinical practice. Thus, the management of patients in the preclinical phase of AD (PPAD) has been identified to be highly important for addressing this concern. PPAD is considered a preclinical manifestation of the early stages of AD and includes subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Developments in magnetic resonance imaging (MRI) technology have led to its demonstration of great potential in the early identification and progression monitoring of PPAD. Thus, in this review, we summarized the concepts, principles and applications of structural and diffusion MRI in the identification of PPAD to provide potential imaging markers that can be used by clinicians in clinical practice.},
}

@article {pmid40918734,
year = {2025},
author = {Sun, X and Lu, Y and Hu, J and Meng, S and Wang, X and Jiang, Q},
title = {Tooth loss impairs cognitive function in SAMP8 mice by aggravating pyroptosis of microglia via the cGAS/STING pathway.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1628520},
pmid = {40918734},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disease among the elderly population. It has been posited that the onset and progression of AD are influenced by a combination of various factors. Occlusal support loss due to tooth loss has been reported to be a risk factor triggering cognitive dysfunction. This study aimed to investigate the relationship between tooth loss and cognitive dysfunction and illustrate the role of pyroptosis in advancing Alzheimer's disease.

METHODS: Male 5-month-old senescence-accelerated mouse strain P8 (SAMP8) mice were divided into two groups (n = 6): the S (sham-operated) and TL (tooth loss) groups. We assessed spatial memory ability using the Y-maze and Novel Object Recognition (NOR) tests. In addition, we performed pathological and molecular biological assessments of the hippocampus to evaluate pyroptosis-related indicators and changes in cGAS/STING. We further verified the correlation between the two in vitro.

RESULTS: The pathological section staining revealed an upregulation of GSDMD, a target protein of pyroptosis, and abnormal activation of the cGAS/STING pathway, particularly in microglia, after tooth loss. In vitro, we demonstrated that the BV2 microglia knockdown STING group improved the inflammatory cascade response and down-regulated the pyroptotic features.

DISCUSSION: These data suggest that the occlusal support loss due to tooth loss induces pyroptosis-related protein deposition, which may be intimately associated with the cGAS/STING signaling pathway. This provides new insights into the treatment and prevention of oral health and cognitive behavioural disorders in the elderly population.},
}

@article {pmid40918343,
year = {2025},
author = {Kaya, B and Çevik, UA and Çiftçi, B and Necip, A and Işik, M and Ay, EN and Yur, S and Özkay, Y and Beydemir, Ş and Kaplancıklı, ZA},
title = {Design, Synthesis, and Molecular Docking Studies of Novel Pyrazoline-Thiazoles as Cholinesterase Dual-Target Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {ACS omega},
volume = {10},
number = {34},
pages = {38427-38439},
pmid = {40918343},
issn = {2470-1343},
abstract = {Ten novel pyrazoline-thiazole derivatives were synthesized and assessed for their potential as acetylcholinesterase and butyrylcholinesterase inhibitors. The structure of the target compounds was characterized by [1]H NMR and [13]C NMR, and purity was determined using HPLC. The in vitro enzyme inhibitory activity assays determined that compounds 3f (IC50 = 0.382 μM) and 3g (IC50 = 0.338 μM) showed good inhibitory activity of acetylcholinesterase (AChE). Compound 3f has a selective inhibitory effect on AChE, while compound 3g has a dual effect, being effective against both AChE and BChE (IC50 = 2.087 μM). The molecular docking results of compound 3g with high inhibitory activity for AChE experimentally showed that it has a strong inhibitory effect close to that of the reference inhibitor tacrine. The compound 3g was found to have the highest activity in its interaction with the BChE (4BDS) protein with a low docking score (-5.555 kcal/mol). Furthermore, the prediction of ADME properties of compounds 3f and 3g was determined through Swiss ADME.},
}

@article {pmid40917662,
year = {2025},
author = {Sun, Z and Li, Y and Qu, X and Wang, L and Zhu, S and Sun, X and Yang, L and Sun, X},
title = {Research trend of functional magnetic resonance imaging in diabetes mellitus research: a visualization and bibliometric analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1539995},
pmid = {40917662},
issn = {1664-2295},
abstract = {BACKGROUND: Understanding the neurological complications associated with diabetes mellitus is essential for developing comprehensive treatment strategies. Functional magnetic resonance imaging (fMRI) is a powerful tool for investigating brain functional and structural changes associated with various conditions, including diabetes mellitus.

OBJECTIVES: To analyze the application trends, research hotspots, and emerging frontiers of fMRI in diabetes mellitus research through a comprehensive bibliometric analysis.

METHODS: A systematic literature search was conducted utilizing the Web of Science Core Collection (WoSCC) database. Bibliometric tools, including VOSviewer (version 1.6.20), CiteSpace (version 6.3.R1), and R (version 4.3.3), were employed for data analysis.

RESULTS: A total of 706 articles about fMRI and diabetes mellitus were published from 1987 to 2024. The United States of America (USA) ranks first (n = 931), followed by China (n = 756) and Germany (n = 270) regarding total publications. Harvard University ranks first in terms of total publications. Among the top ten institutions regarding publications, the majority of articles originated from the USA. The journal Diabetes has the highest number of publications. The author SHAO YI ranks first in total publications, while FRITSCHE ANDREAS ranks first in total citations. The top five keywords identified are "dementia," "risk," "brain," "Alzheimer's disease," and "functional connectivity." Keyword burst analysis indicates that the recent research hotspots included "impairment," "dysfunction," and "diagnosis."

CONCLUSION: Cognitive impairment and dysfunction related to diabetes mellitus, along with Alzheimer's disease and dementia, and their diagnosis were identified as focal areas of research. Future investigations should concentrate on predicting and early diagnosing cognitive function in patients with diabetes mellitus using fMRI. The findings of this study provide a valuable reference for researchers and clinicians seeking to explore the neurological dimensions of diabetes mellitus and develop targeted therapeutic approaches.},
}

@article {pmid40917568,
year = {2025},
author = {Yoon, DM and Plante, DT and Fleming, V and Handen, B and Lao, P and Peven, J and Christian, B and Okonkwo, O and Laymon, C and Ances, B and Hom, C and Helsel, B and Hartley, SL},
title = {Preliminary investigation of obstructive sleep apnea and Alzheimer's disease in down syndrome.},
journal = {Sleep advances : a journal of the Sleep Research Society},
volume = {6},
number = {3},
pages = {zpaf044},
pmid = {40917568},
issn = {2632-5012},
abstract = {This study provided a preliminary examination of indices of obstructive sleep apsnea (OSA) and sleep disruptions in adults with Down syndrome (DS), and their associations with Alzheimer's disease (AD) pathology and symptomatology. A total of 93 adults with DS (aged 25-61 years) from the Alzheimer Biomarker Consortium-DS completed cognitive assessments, MRI and positron emission tomography (PET) scans (assessing amyloid-beta [Aβ] and tau), and a one-night home sleep study using the WatchPAT-300 device. Study partners also reported on depressive symptoms and diagnoses. Correlational analyses examined relationships between sleep variables, PET biomarkers, and AD symptomatology (cognitive functioning and depressive mood), controlling for sociodemographics. A total of 81 participants (87 per cent) completed valid WatchPAT data. Of these, 60 (74 per cent) screened positive for OSA, and an additional 11 had a prior OSA diagnosis and used CPAP during the test night. Nearly half (45 per cent) of those screening positive for OSA had no prior diagnosis, indicating under-detection. Among the 22 participants using OSA treatment, 50 per cent continued to show sleep-disordered breathing, suggesting suboptimal treatment effectiveness. Higher wake percentage and shorter total sleep time were associated with greater Aβ and tau burden. Cognitive performance was negatively associated with wake percentage, total sleep time, and oxygenation indices (minimum oxygen, desaturation, and time ≤ 88 per cent oxygen). Depressive symptoms were negatively related to total sleep time. These findings add preliminary evidence linking sleep disruption and OSA with AD-related pathology and symptomatology. Larger, longitudinal studies are needed to confirm these associations and evaluate whether improving sleep quality and treating OSA may help delay AD onset in this high-risk population.},
}

@article {pmid40917296,
year = {2025},
author = {Önder, S and Biberoğlu, K and Tacal, Ö},
title = {Thionine modulates tau phosphorylation in an Alzheimer's disease cell culture model.},
journal = {Turkish journal of biology = Turk biyoloji dergisi},
volume = {49},
number = {4},
pages = {400-408},
pmid = {40917296},
issn = {1303-6092},
abstract = {BACKGROUND/AIM: Tau protein, which is crucial for sustaining the cytoskeletal network by assisting microtubule construction, contributes significantly to the pathophysiology of Alzheimer's disease (AD). The hyperphosphorylation of tau causes it to detach from microtubules (MTs), leading to the formation of neurofibrillary tangles (NFTs) in neurons, which ultimately results in cell death. Thionine (TH), a cationic phenothiazine-structured compound, has been the topic of extensive research due to its interesting physicochemical properties. It is a common biological dye, especially useful in histology due to its strong affinity for biological membranes. Furthermore, TH serves as a photosensitizer in phototherapy. It has a phenothiazine pharmacophore, which makes it selective against microbial and tumor cells. Our prior studies demonstrated that TH inhibits human plasma butyrylcholinesterase (BChE) by acting as a nonlinear inhibitor and also affects amyloid precursor protein (APP) metabolism in PS70 cells. In the current research, we investigated whether TH modulates the phosphorylation of tau in N2a/APPSwe cells.

MATERIALS AND METHODS: Using flow cytometry, we identified the dose range and treatment time of TH that did not affect the viability of N2a/APPSwe cells. The western blot method was used to investigate the effects of TH on total tau and four key tau phosphorylation sites.

RESULTS: The results indicated that TH reduces tau phosphorylation at residues Ser202/Thr205, Ser396, Ser396/Ser404, and Thr181, which contribute to NFT formation.

CONCLUSION: When all these findings are evaluated together, TH may have a therapeutic potential against AD.},
}

@article {pmid40916557,
year = {2025},
author = {Feng, X and Wang, H},
title = {Antibody Therapies for Alzheimer's Disease: A New Strategy for Targeted Therapy and Blood-Brain Barrier Delivery.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00484},
pmid = {40916557},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and neuronal loss, with pathological hallmarks including Aβ plaque deposition and tau tangles. At present, the early diagnosis and treatment of AD still face great challenges, such as limited diagnostic methods, difficulty in blood-brain barrier (BBB) penetration, complex disease mechanisms, and lack of highly effective targeted therapies. Antibody drugs have shown broad prospects in the field of AD due to their high specificity, engineering and multifunctional therapeutic potential, include targeted Aβ clearance, tau pathological regulation, imaging probes, and blood biomarkers. In the future, with the development of antibody engineering technologies (such as PROTAC-antibody conjugates and antibody-based gene therapies), the precision diagnosis and treatment of AD is expected to usher in new breakthroughs. This article systematically reviews the latest advances in the treatment and diagnosis of AD and discusses their potential for clinical translation.},
}

@article {pmid40916410,
year = {2025},
author = {Algazzawi, H and Abujamai, J and Alshanberi, AM and Satar, R and Ansari, SA},
title = {Role of GSK-3 Inhibition in Alzheimer's Disease Therapy.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050400781250904082943},
pmid = {40916410},
issn = {1875-5828},
abstract = {A serine/threonine kinase with a wide variety of substrates, Glycogen Synthase Kinase-3 (GSK-3) is widely expressed. GSK-3 is a key player in cell metabolism and signaling, modulating numerous cellular functions and playing significant roles in both healthy and diseased states. The two histopathological features of Alzheimer's disease, the intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and the extracellular senile plaques composed of beta-amyloid, have been linked to GSK-3. It alters multiple tau protein locations found in neurofibrillary tangles. Additionally, GSK-3 can react to this peptide and regulate the production of beta-amyloid. The overexpression of GSK-3 in several transgenic models has been linked to tau hyperphosphorylation, neuronal death, and a reduction in cognitive function. It has been shown that lithium, a medication commonly used to treat affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and stops tau phosphorylation. In this review, we provide an overview of the most recent research on the potential of GSK-3 inhibitors for treating Alzheimer's disease.},
}

@article {pmid40916051,
year = {2025},
author = {Le, HT and Lau, ECY and Lu, CY and Hilmer, SN and Jeon, YH and Low, LF and Nguyen, TA and Tan, ECK},
title = {Treatment modifiers and predictors of risperidone response in dementia: An individual participant data meta-analysis of six randomized controlled trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70665},
pmid = {40916051},
issn = {1552-5279},
mesh = {Humans ; *Risperidone/therapeutic use ; Randomized Controlled Trials as Topic ; *Dementia/drug therapy ; *Antipsychotic Agents/therapeutic use ; Aggression/drug effects ; Treatment Outcome ; Male ; Female ; Aged ; },
abstract = {INTRODUCTION: Risperidone is approved for behaviors and psychological symptoms of dementia (BPSD), despite modest efficacy and known risks. Identifying responsive symptoms, treatment modifiers, and predictors is crucial for personalized treatment.

METHOD: A one-stage individual participant data meta-analysis of six randomized controlled trials (risperidone: n = 1009; placebo: N = 712) was conducted. Mixed-effects models assessed treatment effects, modifiers, and predictors, with BPSD measured via the Behavioral Pathology in Alzheimer's Disease scale.

RESULTS: Risperidone showed modest 8 week benefits for aggression (standardized mean difference [SMD]: -0.22; p < 0.001), psychosis (SMD: -0.23; p = 0.001), and anxiety/phobias (SMD: -0.19; p = 0.014), but not for activity, affective, or sleep disturbances. Pharmacokinetic/pharmacodynamic-related factors (e.g., body mass index, endocrine disease, race/ethnicity) potentially modified treatment effects. Week 2 response predicted week 8 improvement (odds ratio: 4.46; p < 0.001).

DISCUSSION: Risperidone provided symptom-specific benefits in reducing aggression, psychosis, and anxiety/phobias. Week 2 response predicted treatment outcomes, while certain patient characteristics may modify treatment response. Further research is needed to optimize the benefit-risk balance and individualize treatment.

HIGHLIGHTS: Risperidone modestly reduces symptoms of psychosis, aggression, and anxiety/phobias. Risperidone shows no effect on activity, affective, or sleep disturbances. Patient factors (body mass index, endocrine disease, race/ethnicity) may affect response. Positive response by week 2 predicts significant improvement later.},
}

Humans
*Risperidone/therapeutic use
Randomized Controlled Trials as Topic
*Dementia/drug therapy
*Antipsychotic Agents/therapeutic use
Aggression/drug effects
Treatment Outcome
Male
Female
Aged

@article {pmid40915373,
year = {2025},
author = {Lei, HP and Yang, X and Hu, YT and Wu, LN and Wei, AH and Yu, L and Liu, TT and Ji, XH and Liu, J and Jin, H and Zhou, SY and Jin, F},
title = {Gastrodin alleviates mitochondrial energy metabolism dysfunction via activating β-catenin/c-Myc/MCT2 signaling in Alzheimer's disease models.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120548},
doi = {10.1016/j.jep.2025.120548},
pmid = {40915373},
issn = {1872-7573},
abstract = {Gastrodia elata, also known as Chijian, belongs to the Orchidaceae family of plants. The "Compendium of Materia Medica" records that Gastrodia elata treats "confused speech, excessive fear, and loss of willpower". Gastrodin (GAS) is the main bioactive component of Gastrodia elata. Research has shown that GAS possesses protective effects on multiple animal models of Alzheimer's disease (AD). However, the exact molecular mechanism of GAS-mediated neuroprotection in AD pathology remains unclear.

AIM OF THE STUDY: This study aims to determine whether GAS exerts neuroprotective effects on AD models through regulating β-catenin/c-Myc/MCT2 signaling axis.

MATERIALS AND METHODS: Behavioral and histopathological tests, including Morris water maze test, Nissl staining, and NeuN immunofluorescence staining in 3×Tg-AD male mice, were used to assess the pharmacological effect of GAS on AD. To investigate the neuroprotective mechanisms of GAS, we established an in vitro AD model using Aβ25-35-treated HT22 cells. The expressions of proteins and mRNA related to the β-catenin/c-Myc signaling axis were determined by western blotting and quantitative PCR. The change in energy metabolism was evaluated by measuring pyruvate, cellular ATP production, and mitochondrial membrane potential (MMP). The molecular mechanism of GAS-mediated neuroprotection was further explored using pharmacological and genetic interventions targeting β-catenin and c-Myc. Transcriptional regulation was interrogated through β-catenin chromatin immunoprecipitation (ChIP) coupled with JASPAR-based motif prediction, while ligand-receptor interactions were characterized by AutoDock-based molecular docking validated through drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA).

RESULTS: In vivo experimental results revealed that GAS ameliorated cognitive impairment in 3×Tg-AD mice, attenuated neuronal damage, and markedly inhibited the downregulation of active-β-catenin, c-Myc, and MCT2 in the hippocampal tissues. In Aβ25-35-challenged HT22 cells, the relevant protein levels of β-catenin/c-Myc signaling axis were reduced, with both mRNA and protein expressions of MCT2 declining, alongside reductions in pyruvate and ATP concentrations. GAS treatment reversed these pathological alterations, while this effect was antagonized by β-catenin and c-Myc inhibitors. Additionally, lentiviral-mediated β-catenin overexpression markedly increased MCT2 mRNA and protein expression in HT22 cells. The results of chromatin immunoprecipitation assay coupled with quantitative PCR and JASPAR-based motif prediction revealed that β-catenin bound to the MCT2 promoter region. Autodock Vina simulation demonstrated that GAS binds to β-catenin with a binding energy of less than -5 kcal/mol. Both DARTS and CETSA experiments showed that the binding of GAS to β-catenin protects the β-catenin protein from degradation.

CONCLUSION: This study demonstrates that GAS plays a protective role in experimental AD models through enhancing MCT2 expression and improving mitochondrial energy metabolism function by activation of the β-catenin/c-Myc/MCT2 signaling axis.},
}

@article {pmid40913913,
year = {2025},
author = {Lee, H and Hossain, MK and Lee, HY and Kumar, V and Shin, SJ and Kim, BH and Park, HH and Son, JG and Moon, M and Kim, HR},
title = {Taurine suppresses Aβ aggregation and attenuates Alzheimer's disease pathologies in 5XFAD mice and patient-derived cerebral organoids.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {191},
number = {},
pages = {118527},
doi = {10.1016/j.biopha.2025.118527},
pmid = {40913913},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is marked by amyloid-beta (Aβ) plaque buildup, tau hyperphosphorylation, neuroinflammation, neuronal loss, and impaired adult hippocampal neurogenesis (AHN). Taurine has shown protective effects in various cellular and animal models of AD, though the molecular mechanisms of free taurine and its effects in patient-derived models remain underexplored. This study evaluates taurine's therapeutic potential using integrated in silico, in vitro, in vivo, and ex vivo approaches. In vitro aggregation assays revealed that taurine (10-100 μM) inhibited Aβ42 fibril formation, with transmission electron microscopy showing looser, amorphous fibrils, particularly at higher doses. Computational simulations further supported that taurine binds stably to Aβ peptide fragments and facilitates the dissociation of Aβ dimers. In HT22 cells, taurine protected against Aβ-induced cytotoxicity. In 5XFAD mice, oral administration of taurine (1000 mg/kg, 4 weeks) significantly reduced Aβ accumulation and hyperphosphorylation of tau at Ser202/Thr205 in the dorsal subiculum. Furthermore, taurine attenuated microgliosis, as evidenced by decreased Iba-1 immunoreactivity, protected against neurodegeneration demonstrated by preserving NeuN-positive neurons, and ameliorated deficit of AHN shown by increasing DCX-positive cells in the subgranular zone of the dentate gyrus. Importantly, in cerebral organoids derived from an AD patient carrying the APOE ε4/ε4 genotype, taurine treatment attenuated Aβ accumulation, decreased tau phosphorylation. These findings highlight taurine's multi-target therapeutic potential targeting amyloid aggregation, tau pathology, neuroinflammation and neurogenesis. Our data support taurine emerges as a promising therapeutic candidate for AD.},
}

@article {pmid40913683,
year = {2025},
author = {Smoller, C and Schiller, E and Yamashita, K and Silverglate, BD and Grossberg, GT},
title = {Current and Emerging Pharmacological Approaches to Agitation in Alzheimer's Disease: A Narrative Review of New and Repurposed Therapies.},
journal = {Drugs},
volume = {},
number = {},
pages = {},
pmid = {40913683},
issn = {1179-1950},
abstract = {This narrative review explores current pharmacological treatments for agitation in Alzheimer's disease (AD). Agitation, a common and difficult-to-manage symptom in AD, often requires targeted intervention. While nonpharmacological methods, such as behavioral therapy and environmental modifications, are considered first line, they may not always be effective. In cases where these approaches fail, pharmacological treatment can become a necessary component of care. Historically, antipsychotics have been the mainstay of pharmacological treatment for agitation in AD; however, safety and efficacy concerns have prompted exploration into alternative treatments. The purpose of this narrative review is to synthesize current literature on pharmacological treatments for agitation in AD with a focus on new and repurposed drugs. It also examines agents that have failed to demonstrate clinical benefit, offering insights into the ongoing challenges of drug development in this area. This review synthesizes recent findings on various drug classes, including anticonvulsants, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), atypical antidepressants, sedatives, anti-dementia drugs, dextromethorphan, and cannabinoids. Both brexpiprazole and risperidone have demonstrated efficacy and received approval from government agencies, including brexpiprazole in the USA and risperidone in parts of Europe. Despite these advances, concerns remain regarding their long-term use and safety profiles. As a result, multiple other therapies are currently being studied as possible alternative solutions. However, no other pharmacological agents are currently approved, underscoring the need for further research on safe and effective options for this vulnerable population.},
}

@article {pmid40913351,
year = {2025},
author = {Peng, D and Wei, P and Li, Z and Wei, R and Li, H and Li, S},
title = {The Role of P62/Nrf2/Keap1 Signaling Pathway in Lead-Induced Neurological Dysfunction.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70566},
doi = {10.1111/cns.70566},
pmid = {40913351},
issn = {1755-5949},
support = {82160626//National Natural Science Foundation of China/ ; 81803281//National Natural Science Foundation of China/ ; },
mesh = {*Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; Animals ; *Signal Transduction/drug effects/physiology ; *Lead/toxicity ; *Sequestosome-1 Protein/metabolism ; Male ; Oxidative Stress/drug effects/physiology ; Mice ; Reactive Oxygen Species/metabolism ; Neurons/drug effects/metabolism ; Cells, Cultured ; Rats ; Autophagy/drug effects ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Lead (Pb) exposure is recognized for its contribution to the development of neurodegenerative diseases. However, the precise mechanisms underlying Pb-induced neurological dysfunction remain elusive. This study aimed to investigate the role of oxidative stress and the autophagy-related P62/kelch like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in neuronal impairment caused by Pb.

METHODS: By employing both in vivo and in vitro approaches, we explored the involvement of the P62/Nrf2/Keap1 pathway in Pb-induced neurotoxicity.

RESULTS: Our findings demonstrated that Pb exposure triggers excessive production of reactive oxygen species (ROS), upregulates Keap1 protein expressions, promotes Nrf2 degradation, and inhibits expression of antioxidant proteins such as heme Oxygenase-1 (HO-1) and glutathione peroxidase (GPx), resulting in oxidative damage in neurons. Furthermore, we observed that the autophagy protein P62 disrupts the normal autophagy process by interacting with the Nrf2/Keap1 axis, leading to an accumulation of Tau, a protein associated with Alzheimer's disease (AD), ultimately resulting in neurodegeneration. However, treatment with the antioxidant N-acetylcysteine, Nrf2 activator Artemisitene, and autophagy activator Rapamycin attenuated these detrimental changes.

CONCLUSION: The P62/Nrf2/Keap1 pathway mediates Pb-induced neuronal dysfunction and highlights its potential as a therapeutic target for mitigating the neurodegenerative effects associated with Pb exposure.},
}

*Kelch-Like ECH-Associated Protein 1/metabolism
*NF-E2-Related Factor 2/metabolism
Animals
*Signal Transduction/drug effects/physiology
*Lead/toxicity
*Sequestosome-1 Protein/metabolism
Male
Oxidative Stress/drug effects/physiology
Mice
Reactive Oxygen Species/metabolism
Neurons/drug effects/metabolism
Cells, Cultured
Rats
Autophagy/drug effects
Mice, Inbred C57BL

@article {pmid40912996,
year = {2025},
author = {Greeley, D and Nash, M and Herskowitz, B and Kim, F and Rock, J and Prins, N and Kim, S and Xi, T and Busam, JA and Tete, B and Choung, JJ and Sha, SJ},
title = {A phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100337},
doi = {10.1016/j.tjpad.2025.100337},
pmid = {40912996},
issn = {2426-0266},
abstract = {BACKGROUND: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer's disease (AD).

OBJECTIVES: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer's disease (AD).

DESIGN: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States.

PARTICIPANTS: Adults aged 55-80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer's Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26.

INTERVENTION: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension.

MEASUREMENTS: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined.

RESULTS: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo.

CONCLUSION: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo.

TRIAL REGISTRATION: clinicaltrials.gov; NCT03625622.},
}

@article {pmid40912535,
year = {2025},
author = {Cheng, F and Gao, H and Yan, B and Chen, F and Lei, P},
title = {From Disinfectant to Neurodegeneration: Integrating Machine Learning and Mendelian Randomization Reveals Triclosan as A Novel Environmental Risk Factor for Alzheimer's Disease.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {127068},
doi = {10.1016/j.envpol.2025.127068},
pmid = {40912535},
issn = {1873-6424},
abstract = {This study systematically investigated the association between triclosan (TCS) exposure and Alzheimer's disease (AD) risk via integrated bioinformatics approaches. TCS-AD-related genes were identified using bioinformatics tools and public databases, followed by the screening of key genes through multi-model machine learning algorithms (LASSO, SVM-RFE, RF) to mitigate random errors in small sample sizes. DRD2 was confirmed as the most robust core gene by LASSO confidence interval analysis and SHAP evaluation, while APP and SLC6A3 were validated through cross-method intersection. Findings from functional enrichment analysis, Mendelian randomization, and molecular docking demonstrated that TCS may affect AD pathogenesis through these key genes. Moreover, a stable AD risk scoring model and predictive formula were developed via logistic regression analysis of T-A-Key Genes. This study constitutes an innovative and transformative research endeavor. Building upon the understanding of TCS-induced neurotoxicity, it extends to the clinical translational direction of predicting AD onset risk, thereby establishing a quantitative association model of "environmental exposure-core genes-disease risk. " It not only provides novel evidence for the potential role of TCS neurotoxicity as an environmental pathogenic factor in AD, emphasizing the necessity of prioritizing risk management of daily chemical exposure in AD prevention and treatment, but also offers a scientific foundation for the formulation of public health policies aimed at preventing long-term TCS exposure.},
}

@article {pmid40912368,
year = {2025},
author = {Wang, J and Qiao, Z and Cao, X and Li, H and Wang, Y and Jiao, Q and Chen, X and Du, X},
title = {G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117303},
doi = {10.1016/j.bcp.2025.117303},
pmid = {40912368},
issn = {1873-2968},
abstract = {Parkinson's Disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, is clinically characterized by resting tremor, rigidity and postural balance disorder. Its pathological essence is the progressive degenerative death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a significant decrease in striatal dopamine (DA) levels. This results in the dysfunction of basal ganglia-thalamus-cortex (BGTC) circuit. This circuit is the core neural circuit of motor control, and its abnormality not only directly causes the motor symptoms of PD, but also participates in the cascade of disease progression through the disorder of neurotransmitter signals. At present, DA replacement therapy and DA receptors (DARs) agonists are still the main methods of clinical treatment, but single therapy cannot fully correct the imbalance of other neurotransmitter systems, which has significant limitations in long-term efficacy and symptom management. G protein-coupled receptors (GPCRs), as the largest family of membrane proteins, have become important targets for PD treatment due to their extensive participation in physiological regulatory networks and excellent drug development potential. These transmembrane signaling molecules play important roles in multiple key nodes in the pathological process of PD by precisely regulating the release of neurotransmitters, the maintenance of synaptic plasticity and the dynamic balance of neural circuits. Here, we review the transition of BCTG in the context of PD and then focus on the pathological cascade of GPCRs mediating PD in this loop. Finally, we update the clinical trials or approvals of GPCR drugs under investigation for the treatment of PD.},
}

@article {pmid40912064,
year = {2025},
author = {Ali, N and Al-Rejaie, SS and Babu, MA and Nayak, P and VenuPrasad, KD and Mohany, M and Singh, TG and Akhter, MS and Fareed, M and Tyagi, Y and Bansal, N and Puri, S},
title = {Exploring the bioactive constituents from spices targeting N-methyl-d-aspartate receptors: An in silico and in vitro approach to identify druggable leads against neurological disability.},
journal = {Bioorganic & medicinal chemistry},
volume = {130},
number = {},
pages = {118378},
doi = {10.1016/j.bmc.2025.118378},
pmid = {40912064},
issn = {1464-3391},
abstract = {N-methyl-d-aspartate (NMDA) receptors are validated druggable targets for the treatment of Alzheimer's and other associated neurological conditions, particularly in individuals with disabilities. Considering the excitotoxicity associated with NMDA receptors, which leads to neuronal damage, cognitive impairment, and limitations of current therapeutic regimens, better therapeutic candidates are required. One of the validated drug discovery approaches is computer-assisted drug discovery, supplemented by molecular docking, mechanics, and dynamics. To this end, we curated 134 bioactive constituents derived from spices. These were subjected to high-throughput virtual screening (HTVS) considering the pharmacophoric features of the NMDA receptor. Molecular docking, followed by molecular mechanics and dynamics, indicated that curcumin and quercetin could plausibly bind to the NMDA receptor in comparison to memantine. In vitro ELISA-based analysis revealed that curcumin may inhibit the NMDA receptor with an IC50 of 2.36 μM compared to memantine's 736.48 nM, employed as a positive control. However, targeting the neuronal receptor NMDA requires that the ligand efficiently cross the blood-brain barrier (BBB). To overcome this challenge, we performed a rational bioisosteric replacement strategy to potentially optimize the pharmacokinetic features of curcumin without affecting its NMDA binding. We generated 150 bioisosteres of curcumin, and through extensive computational analyses, the top 5 scoring molecules were further validated via a molecular dynamics approach. However advantageous, in the present work, curcumin or its proposed derivatives have not been corroborated by extensive biological investigation. It is a prototype study to identify the druggable leads from the spices that have the potency to interact and inhibit NMDA. Owing to this, the mechanism of action is not fully elucidated. Further, the work upon validation (biologically) may serve as a useful pharmacophore (tool molecule) using which NMDA may be downregulated. The designed derivatives thus open avenues to synthesize and biologically test them against NMDA inhibition, plausibly establishing their roles in Alzheimer's and related disabilities.},
}

@article {pmid40911712,
year = {2025},
author = {Wang, G and Li, Y and McDade, E and Xiong, C and Hartz, SM and Bateman, RJ and Morris, JC and Schneider, LS and , },
title = {Clinical progression on CDR-SB©: Progression-free time at each 0.5 unit level in dominantly inherited and sporadic Alzheimer's disease populations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70643},
doi = {10.1002/alz.70643},
pmid = {40911712},
issn = {1552-5279},
support = {U19AG032438//The Dominantly Inherited Alzheimer Network/ ; SG-20-690363-DIAN//National Institute on Aging (NIA), the Alzheimer's Association/ ; HI21C0066//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//Department of Defense/ ; U01AG042791//National Institute on Aging of the National Institutes of Health/ ; U01AG042791-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG046179//National Institute on Aging of the National Institutes of Health/ ; R01AG053267//National Institute on Aging of the National Institutes of Health/ ; R01AG053267-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG068319//National Institute on Aging of the National Institutes of Health/ ; 1U01AG059798//National Institute on Aging of the National Institutes of Health/ ; P30AG066530//National Institute on Aging of the National Institutes of Health/ ; U01AG042791//National Institute on Aging of the National Institutes of Health/ ; U01AG042791-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG046179//National Institute on Aging of the National Institutes of Health/ ; R01AG053267//National Institute on Aging of the National Institutes of Health/ ; R01AG053267-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG068319//National Institute on Aging of the National Institutes of Health/ ; 1U01AG059798//National Institute on Aging of the National Institutes of Health/ ; P30AG066530//National Institute on Aging of the National Institutes of Health/ ; U01AG052564//National Institute on Aging of the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/diagnosis ; *Disease Progression ; Female ; Male ; Aged ; *Mental Status and Dementia Tests ; Cohort Studies ; Middle Aged ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Clinical Dementia Rating Sum of Boxes (CDR-SB) is a reliable and clinically meaningful composite for assessing treatment effects in Alzheimer's disease (AD) clinical trials. Small CDR-SB differences at the end of a trial often lead to controversy in deriving clinically meaningful interpretations.

METHODS: We estimated progression-free time (PFT) participants remained at each 0.5 unit CDR-SB increment in dominantly inherited AD (DIAD) and sporadic AD populations, evaluating its potential as an alternative measure of treatment effects.

RESULTS: PFT is longer at CDR-SB ≤ 2.0 (1-2 years) and shorter at CDR-SB ≥ 5 (≤ 0.33) in the Alzheimer's Disease Neuroimaging Initiative cohort. The DIAD cohort showed similar but shorter times. Using PFT, continuous lecanemab treatment for 3 years is estimated to delay disease progression by 0.62 years in the sporadic population.

DISCUSSION: PFT provides a benchmark for expressing clinical progression and treatment effects and can be applied particularly during open-label extensions and single-arm trials without placebo comparisons.

HIGHLIGHTS: We estimated the progression-free time at each 0.5 unit Clinical Dementia Rating Sum of Boxes increment in dominantly inherited Alzheimer's disease (AD) and sporadic AD populations. We proposed using progression-free time to estimate treatment effects in open-label extension or single-arm studies. If further validated, progression-free time could serve as a benchmark for assessing clinical progression and treatment effects.},
}

Humans
*Alzheimer Disease/genetics/drug therapy/diagnosis
*Disease Progression
Female
Male
Aged
*Mental Status and Dementia Tests
Cohort Studies
Middle Aged
Neuropsychological Tests

@article {pmid40911700,
year = {2025},
author = {Maria, and Khan, A and Ajaj, R and Rauf, A and , and Shah, ZA and Ahmad, Z and Hemeg, HA and Rashid, U},
title = {Secondary metabolites isolated from Fernandoa adenophylla (Wall. ex G.Don) steenis as multitarget inhibitors of cholinesterases for the treatment of Alzheimer's Disease, followed by molecular docking studies.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0331119},
doi = {10.1371/journal.pone.0331119},
pmid = {40911700},
issn = {1932-6203},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/isolation & purification ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy/enzymology ; Butyrylcholinesterase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; Humans ; *Plant Extracts/chemistry/pharmacology ; Secondary Metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder categorized by the progressive loss of cognitive function, with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as key therapeutic targets. In this study, we report the isolation, characterization, and evaluation of the cholinesterase inhibitory potential of phytochemicals from Fernandoa adenophylla (Wall. ex G. Don) Steenis, a plant known for its medicinal properties. Using in-vitro enzyme inhibition assays, we identified five bioactive compounds, including lapachol (1), α-lapachone (2), peshawaraquinone (3), dehydro-α-lapachone (4), and an indanone derivative (5), which demonstrated significant inhibition of AChE and BuChE. The compounds exhibited varied inhibitory potency, with peshawaraquinone (3) showing the most promising AChE (IC50 = 0.90 ± 0.04 µM) and BuChE (IC50 = 8.39 ± 0.14 µM) inhibition, followed by dehydro-α-lapachone (4), which exhibited an AChE IC50 value of 2.64 ± 0.08 µM. Further, the selectivity index (SI) for AChE over BuChE was highest for dehydro-α-lapachone (SI = 21.1), suggesting its potential as a selective inhibitor. Molecular docking studies provided insights into the binding interactions between these compounds and the enzyme active sites, highlighting key interactions that may contribute to their inhibitory activity. These findings suggest that phytochemicals from F. adenophylla possess significant cholinesterase inhibition potential and may serve as leads for the development of novel therapeutic agents for Alzheimer's disease.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/isolation & purification
Molecular Docking Simulation
*Alzheimer Disease/drug therapy/enzymology
Butyrylcholinesterase/metabolism/chemistry
Acetylcholinesterase/metabolism/chemistry
Humans
*Plant Extracts/chemistry/pharmacology
Secondary Metabolism

@article {pmid40911470,
year = {2025},
author = {Yamamoto, N and Yuzu, K and Morishima, K and Inoue, R and Sugiyama, M and Koyama, D and Chatani, E},
title = {Targeting Both Monomer and Oligomer with Fibrinogen Efficiently Suppresses Amyloid Fibril Formation and Cell Toxicity of Amyloid β 1-42.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00562},
pmid = {40911470},
issn = {1948-7193},
abstract = {The development of drugs for Alzheimer's disease, which accounts for over half of all dementia cases, remains challenging. Amyloid β 1-42 (Aβ42) is widely recognized for its deposition in the brains of patients with Alzheimer's disease. Furthermore, Aβ42-induced cell toxicity likely plays a role in disease onset. Molecular species present in the early stages, such as monomers and oligomers, are appropriate therapeutic targets for suppressing amyloid fibril formation and cell toxicity. In this study, we investigated the effects of bovine fibrinogen (bFg) and human fibrinogen (hFg) since these molecules have been known to exhibit chaperone-like activities. Our findings indicate that bFg exerts a strong inhibitory effect on amyloid fibril formation. Dot blot assays, analytical ultracentrifugation (AUC), and atomic force microscopy (AFM) suggest that bFg interacts with both Aβ42 monomers and oligomers. In contrast, human fibrinogen (hFg), which interacts only with oligomers, exhibits a weaker inhibitory effect on amyloid fibril formation. Moreover, bFg significantly rescued cells from Aβ42-induced toxicity, whereas hFg provided only partial protection. These findings underscore the potential of molecules targeting early stage Aβ42 species as promising candidates for Alzheimer's disease treatment.},
}

@article {pmid40911101,
year = {2025},
author = {Qian, J and Ren, S and Ren, T and Shi, R and Qiao, L and Kang, J},
title = {Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.},
journal = {Neurochemical research},
volume = {50},
number = {5},
pages = {287},
pmid = {40911101},
issn = {1573-6903},
support = {202310472004//the College Students' Innovation and Entrepreneurship Training Program/ ; 82071326//the National Natural Science Foundation of China/ ; 232102310288//Key Technologies R&D Program of Henan Province/ ; 252300421395//Natural Science Foundation of Henan/ ; 505511, XYBSKYZZ202124, 506017//Doctoral Scientific Research Foundation of Xinxiang Medical University/ ; },
mesh = {Humans ; *Autophagy/physiology/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy ; *Astrocytes/metabolism/pathology/drug effects ; Animals ; Oxidative Stress/physiology ; },
abstract = {Astrocytes, the most abundant and functionally diverse glial cell type in the brain, play a crucial role in maintaining cellular homeostasis and promoting neuronal survival. Autophagy is the process of transferring senescent, denatured, or damaged proteins and organelles from cells to lysosomes for degradation. However, recent research on autophagy in the central nervous system has focused on neurons. In this paper, we reviewed the latest findings on astrocyte autophagy and its mechanisms in regulating neurodegenerative disorders. It influences the pathological processes of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other synucleinopathies (including dementia with Lewy bodies and Parkinson's disease dementia) by regulating oxidative stress and inflammatory responses, as well as aberrant protein aggregation and folding. Furthermore, we listed medications that can prevent or treat neurodegenerative disorders by modulating astrocyte autophagy pathways, providing new insights into preventive and therapeutic strategies for neurodegenerative diseases.},
}

Humans
*Autophagy/physiology/drug effects
*Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy
*Astrocytes/metabolism/pathology/drug effects
Animals
Oxidative Stress/physiology

@article {pmid40910917,
year = {2025},
author = {Xin, YX and Xiao, YL},
title = {[Research progress on the relationship between traumatic brain injury and neurogenic lower urinary tract dysfunction].},
journal = {Zhonghua nan ke xue = National journal of andrology},
volume = {31},
number = {7},
pages = {650-653},
pmid = {40910917},
issn = {1009-3591},
mesh = {Humans ; *Brain Injuries, Traumatic/complications ; *Urinary Bladder, Neurogenic/etiology ; Risk Factors ; },
abstract = {Urinary dysfunction caused by central nervous system or peripheral nerve disease represents a significant global medical and social problem. Neurologic abnormalities, including traumatic brain injury (TBI), stroke, Alzheimer's disease, and Parkinson's disease, have been identified as potential risk factors for neurogenic urinary tract dysfunction. The relationship between TBI and neurogenic lower urinary tract dysfunction (NLUTD) will be introduced in this article, with the mechanisms, clinical manifestations, diagnostic methods, and treatment strategies of NLUTD after TBI being evaluated as well, which provides a reference for the diagnosis and treatment.},
}

Humans
*Brain Injuries, Traumatic/complications
*Urinary Bladder, Neurogenic/etiology
Risk Factors

@article {pmid40910390,
year = {2025},
author = {Frederiksen, KS and Gramkow, MH and Hasselbalch, SG and Law, I and Waldemar, G},
title = {[Anti-amyloid antibodies for the treatment of early-stage Alzheimer's disease].},
journal = {Ugeskrift for laeger},
volume = {187},
number = {35},
pages = {},
doi = {10.61409/V03250217},
pmid = {40910390},
issn = {1603-6824},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/immunology ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; },
abstract = {Alzheimer's disease is the most common neurodegenerative dementia disorder and is associated with several negative health outcomes. Current treatment consists of symptomatic treatment and supportive measures. However, advances have led to the development of antibodies towards beta-amyloid, which likely plays a pivotal role in the pathophysiology. Lecanemab and donanemab have shown efficacy in the early stages of Alzheimer's disease but are also associated with a risk of cerebral haemorrhages and oedema. The introduction of these antibodies will require adjustment of diagnostic and management pathways as discussed in this review.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/immunology
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
*Antibodies, Monoclonal/therapeutic use/adverse effects

@article {pmid40910338,
year = {2025},
author = {Navarra, AN and Wang, LA and Al-Sahlani, H and Liu, AJ and Doraiswamy, PM},
title = {Severe Persistent Urinary Retention Following Treatment With Intravenous Lecanemab: Urinary Retention With IV Lecanemab.},
journal = {Pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1002/phar.70060},
pmid = {40910338},
issn = {1875-9114},
abstract = {Lecanemab is an amyloid-targeted antibody indicated for treating patients with amyloid-confirmed early Alzheimer's Disease in mild dementia or mild cognitive impairment stages. We report here a case of a subject with early stage of Alzheimer's Disease dementia, amyloid positive, who developed severe acute urinary retention following his first dose of intravenous lecanemab. His urinary retention resolved after a week but recurred following the second intravenous dose 2 weeks later. Lecanemab was discontinued, but the urinary retention has persisted for 8 months indicating possible permanent adverse impact on the bladder. The Naranjo causality probability score was 6. The incidence of urinary retention with intravenous lecanemab is not known but given that elderly patients with dementia may have multiple risks for bladder dysfunction, clinicians should remain vigilant. It is hoped that newer formulations, such as subcutaneous lecanemab, may prove safer in such patients.},
}

@article {pmid40910212,
year = {2025},
author = {Zhang, YY and Cheng, YY and Guan, W},
title = {Betaine, a Potential Therapeutic Alternative for the Treatment of Depression.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501394957250818110931},
pmid = {40910212},
issn = {1873-5592},
abstract = {Depression is a debilitating psychiatric disorder characterized by loss of interest, anhedonia, and social isolation, which is projected to become the leading cause of disability worldwide by 2030. Despite the greater economic and social burden imposed by depression, the precise pathophysiology underlying the development of depression remains elusive. Betaine (N, N, N-trimethylglycine), an amino acid derivative, is widely distributed in various animals and plants and has been shown to have numerous beneficial effects, including antioxidant activities, anti-inflammatory functions, regulation of energy metabolism, and reduction of endoplasmic reticulum stress. It has been used to treat Alcohol-Associated Liver Disease (AALD), type 2 diabetes, cancer, obesity, and Alzheimer's Disease (AD). Interestingly, accumulating evidence has shown that betaine exerts a significant role in alleviating depressive-like behavior in patients and animals resulting from chronic stress. Although the antidepressant effects of betaine have not been compared with traditional antidepressants with insufficient verification, based on the neurobiological mechanisms of depression, it may be a potential alternative medicine for the treatment of depression. This is the first review aiming to provide a comprehensive overview of the remarkable effects of betaine in the pathophysiology of depression. These pieces of evidence are of great importance for deepening our understanding of the antidepressant mechanism of betaine, so as to develop betaine supplements for the supplementary treatment of depression.},
}

@article {pmid40910023,
year = {2025},
author = {Shahid, SB and Kaikaus, M and Kabir, MH and Yousuf, MA and Azad, AKM and Al-Moisheer, AS and Alotaibi, N and Alyami, SA and Bhuiyan, T and Moni, MA},
title = {Novel deep learning for multi-class classification of Alzheimer's in disability using MRI datasets.},
journal = {Frontiers in bioinformatics},
volume = {5},
number = {},
pages = {1567219},
pmid = {40910023},
issn = {2673-7647},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is one of the most common neurodegenerative disabilities that often leads to memory loss, confusion, difficulty in language and trouble with motor coordination. Although several machine learning (ML) and deep learning (DL) algorithms have been utilized to identify Alzheimer's disease (AD) from MRI scans, precise classification of AD categories remains challenging as neighbouring categories share common features.

METHODS: This study proposes transfer learning-based methods for extracting features from MRI scans for multi-class classification of different AD categories. Four transfer learning-based feature extractors, namely, ResNet152V2, VGG16, InceptionV3, and MobileNet have been employed on two publicly available datasets (i.e., ADNI and OASIS) and a Merged dataset combining ADNI and OASIS, each having four categories: Moderate Demented (MoD), Mild Demented (MD), Very Mild Demented (VMD), and Non Demented (ND).

RESULTS: Results suggest the Modified ResNet152V2 as the optimal feature extractor among the four transfer learning methods. Next, by utilizing the modified ResNet152V2 as a feature extractor, a Convolutional Neural Network based model, namely, the 'IncepRes', is proposed by fusing the Inception and ResNet architectures for multiclass classification of AD categories. The results indicate that our proposed model achieved a standard accuracy of 96.96%, 98.35% and 97.13% for ADNI, OASIS, and Merged datasets, respectively, outperforming other competing DL structures.

DISCUSSION: We hope that our proposed framework may automate the precise classifications of various AD categories, and thereby can offer the prompt management and treatment of cognitive and functional impairments associated with AD.},
}

@article {pmid40909873,
year = {2025},
author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J},
title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.},
journal = {FASEB bioAdvances},
volume = {7},
number = {8},
pages = {e70041},
pmid = {40909873},
issn = {2573-9832},
abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.},
}

@article {pmid40908886,
year = {2025},
author = {Singh, T and Yadav, R and Hazra, S},
title = {Atomically Dispersed Ru Catalyst Locked in Knitting Aryl Network Polymers: A Robust Heterogeneous Catalyst for Borrowing Hydrogenation in Aqueous Micelles.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c09711},
pmid = {40908886},
issn = {1944-8252},
abstract = {Fabrication of water-stable and atomically dispersed ruthenium catalysts for sustainable borrowing hydrogenation (BH) reactions is a long-standing challenge. Herein, we developed an atomically dispersed Ru catalyst that has been successfully employed for BH reactions in aqueous micelles under mild conditions. The micellar cooperativity with the hydrophobic knitted aryl polymers (KAPs) led to the formation of microconfinements, which act as the confined space for catalysis in water. The catalyst was characterized by using various techniques such as transmission electron microscopy (TEM), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC-HAADF-STEM), X-ray photoelectron spectroscopy (XPS), and X-ray absorption spectroscopy (XAS). Confocal laser scanning microscopy (CLSM) and fluorescence lifetime imaging microscopy (FLIM) have been used to understand the role of micelles, reagents, and materials in the generation of confined space in water. The catalyst was found to be recyclable for five cycles without a significant loss of its catalytic activity. We have also demonstrated a 1 g scale reaction for the alkylation of acetophenone and synthesis of Donepezil, a marketed drug for the treatment of Alzheimer's disease, using our method.},
}

@article {pmid40908772,
year = {2025},
author = {Faysal, M and Zehravi, M and Sutradhar, B and Al Amin, M and Shanmugarajan, TS and Arjun, UVNV and Ethiraj, S and Durairaj, A and Dayalan, G and Ahamad, SK and Rab, SO and Raman, K and Emran, TB},
title = {The Microbiota-Gut-Brain Connection: A New Horizon in Neurological and Neuropsychiatric Disorders.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70593},
doi = {10.1111/cns.70593},
pmid = {40908772},
issn = {1755-5949},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/microbiology/metabolism/therapy ; *Nervous System Diseases/microbiology/metabolism/therapy ; *Brain/metabolism ; Animals ; Dysbiosis ; *Brain-Gut Axis/physiology ; Probiotics ; },
abstract = {INTRODUCTION: The microbiota-gut-brain axis (MGBA), a complex two-way connection between the gut microbiota and the brain, has become a key regulator of neurological and neuropsychiatric disorders. Neurological disorders and gut microbiota dysbiosis are linked to these diseases. Changes in gut microbiota can lead to neurotransmitter imbalances, oxidative stress, and neuroinflammation. Gut dysbiosis may contribute to the development of diseases such as depression, autism, schizophrenia, bipolar disorder, Parkinson's disease, Alzheimer's disease, dementia, multiple sclerosis, epilepsy, anxiety, and autism spectrum disorders through immunological regulation, neuroinflammation, and neurotransmitter metabolism changes.

METHOD: This review systematically sourced articles related to microbiota gut brain axis, neurological disorders, neuropsychiatric disorders and clinical studies from major medical databases, including Scopus, PubMed, and Web of Science.

RESULTS: This review explores the molecular processes underlying MGBA interactions, including vagus nerve signaling, systemic immunological responses, and metabolites produced by microorganisms. The discussion explores the potential of microbiome-targeted treatments like fecal microbiota transplantation, probiotics, and prebiotics as effective treatment methods. The comprehension of the MGBA can revolutionize neurology and psychiatry, introducing innovative diagnostic and therapeutic approaches. Multiple elements, including diet, metabolism, age, stress, and medications, shape the human gut microbiota, and intestinal imbalances can lead to CNS diseases. The MGBA interacts with gut bacteria, and gut dysbiosis is associated with neurological disorders.

CONCLUSIONS: The review demonstrates the correlation between gut microbiota and neurologically associated diseases, highlighting its importance in neurogenesis, mental development, emotions, and behaviors. MGBA, mediated by microbial metabolites, affects brain function and neuroinflammation. Interventions like fetal microbiota transplantation, probiotics, and prebiotics can improve microbial balance, but more clinical research is needed.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Mental Disorders/microbiology/metabolism/therapy
*Nervous System Diseases/microbiology/metabolism/therapy
*Brain/metabolism
Animals
Dysbiosis
*Brain-Gut Axis/physiology
Probiotics

@article {pmid40908698,
year = {2025},
author = {Singh, A and Maheshwari, S and Ansari, VA and Verma, A and Ansari, TM and Akhtar, J and Ahsan, F and Vishwakarma, VK and Wasim, R},
title = {Dendrimers: Advancing Therapeutic Strategies for Dementia.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098343913250818112618},
pmid = {40908698},
issn = {1874-6128},
abstract = {Dementia, characterized by a progressive decline in cognitive function, poses a significant challenge to global healthcare systems, with current therapeutic approaches offering limited efficacy. The development of nanotechnology-based drug delivery systems has introduced promising avenues for enhancing the treatment of neurodegenerative disorders such as Alzheimer's disease. Dendrimers, with their highly branched, nanoscale structure, provide an innovative platform for targeted drug delivery to the brain. Dendrimers serve as nanoscale drug carriers that facilitate controlled drug release, enhance bioavailability, and improve penetration across the blood-brain barrier (BBB), leading to superior therapeutic efficacy in neurodegenerative disorders. In particular, dendrimers can encapsulate both hydrophilic and hydrophobic drugs, increasing their stability and minimizing systemic side effects. This review explores the unique properties of dendrimers, focusing on their potential as drug delivery vehicles in dementia treatment. We also highlight advancements in the design and application of dendrimer-based therapeutics, emphasizing their role in targeting key pathological mechanisms underlying dementia. Through these approaches, dendrimers represent a promising strategy for developing more effective and personalized treatment modalities for patients suffering from cognitive impairment and dementia.},
}

@article {pmid40908696,
year = {2025},
author = {Paul, S and Tiwari, P and Dubey, S},
title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.},
journal = {Protein and peptide letters},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298665391103250825102319},
pmid = {40908696},
issn = {1875-5305},
abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management.

METHODS: A comprehensive literature review spanning recent/current was conducted using PubMed, Scopus, and ScienceDirect. Studies focusing on enzyme-based targets, high-throughput screening, and molecular docking in neurodegeneration were included. Thematic synthesis was employed to categorize findings based on enzyme class, disease relevance, and therapeutic outcomes.

RESULTS: Key enzyme families such as kinases, proteases, and oxidoreductases were identified as pivotal modulators in disease progression. Emerging enzyme-targeted compounds demonstrated enhanced bioavailability, blood-brain barrier permeability, and disease-specific efficacy. Novel screening platforms and computational modeling enabled the precise selection of inhibitors, significantly improving the therapeutic index and reducing off-target effects.

DISCUSSION: Targeting enzymes implicated in neuroinflammation, oxidative stress, and protein misfolding has shown disease-modifying potential. Integrating precision drug discovery tools, such as AI-assisted modeling and enzyme kinetics, supports rational drug design. However, translational challenges persist due to variability in enzyme expression and disease heterogeneity.

CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.},
}

@article {pmid40908524,
year = {2025},
author = {Oba, GMJ and Sahu, R and Shah, K and Paliwal, D and Kumar Sah, A and Thakur, A},
title = {Current Developments in the Pharmacological Activities and Synthesis of Carbazole Derivatives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575407122250822095143},
pmid = {40908524},
issn = {1875-5607},
abstract = {The growing prevalence of multidrug resistance and its detrimental effects pose a significant threat to public health, which is one reason for the current interest in the introduction of novel agents. To combat this adverse effect and drug resistance, numerous drugs have been developed over time, and their safety is still being evaluated; derivatives or medications based on the carbazole moiety are one of the key contributors. Therefore, this review explores carbazole-based derivatives as possible drugs to treat Alzheimer's, diabetes, inflammation, cancer, and many more, along with their synthetic schemes, SARs, and activity. Some of the carbazole-based drugs available in the market and under clinical trials are also tabulated. By integrating this insight, describe how these compounds are being reinvented as targeted therapeutic agents. This comprehensive analysis is designed to guide researchers in developing next-generation drugs to address various challenges and leverage the unique pharmacological properties of carbazole-derived drugs.},
}

@article {pmid40908201,
year = {2025},
author = {Jung, JH and Kong, N and Lee, S and , },
title = {Pulse pressure as a predictor of Alzheimer's disease biomarkers and cognitive decline: The moderating role of APOE ε4.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100363},
doi = {10.1016/j.tjpad.2025.100363},
pmid = {40908201},
issn = {2426-0266},
abstract = {BACKGROUND: Elevated pulse pressure (PP), indicative of arterial stiffness, has been implicated in cognitive impairment and Alzheimer's disease (AD) pathology. However, its role in preclinical AD and interactions with genetic risk factors like apolipoprotein E ε4 (APOE4) remain unclear.

OBJECTIVES: To investigate the association between baseline PP and AD biomarkers (amyloid-beta (Aβ) and tau) and cognitive decline, and to determine whether APOE4 carrier status moderates these relationships.

DESIGN: Prospective cohort study and secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) randomized clinical trial SETTING: Multicenter observational cohort and randomized clinical trial conducted at 67 sites across the United States, Canada, Australia, and Japan.

PARTICIPANTS: This study included 1690 cognitively unimpaired older adults from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants underwent baseline PP assessment, Aβ and tau PET imaging, and cognitive testing with longitudinal follow-up over 240 weeks.

MEASUREMENTS: Blood pressure was measured at baseline, with PP calculated as the difference between systolic and diastolic pressures. AD pathologies were assessed through Aβ PET imaging using 18F-Florbetapir, and regional tau deposition in inferior temporal and meta-temporal regions using 18F-Flortaucipir PET imaging. Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite (PACC).

RESULTS: Higher baseline PP was significantly associated with increased Aβ (β = 0.078; p = 0.001), inferior temporal tau (β = 0.110; p = 0.032), and meta-temporal tau deposition (β = 0.116; p = 0.022). In longitudinal analyses, elevated PP predicted greater decline in PACC scores (β = -0.020; p < 0.001). APOE4 status moderated these associations, with significant effects of PP on tau deposition and cognitive decline observed exclusively among APOE4 carriers. Mediation analysis indicated that tau deposition significantly mediated the association between PP and cognitive decline (indirect effect β = -0.068; 95 % CI [-0.126, -0.011]).

CONCLUSIONS: Elevated PP is associated with increased AD biomarker burden and accelerated cognitive decline in cognitively unimpaired older adults, particularly among APOE4 carriers. Our study suggests that arterial stiffness may contribute to AD pathogenesis and progression via tau pathology. These results highlight the potential of vascular health management as an early intervention target for AD prevention, especially in genetically at-risk populations.},
}

@article {pmid40907816,
year = {2025},
author = {Rai, S and Nair, A and Saleem, Z and Ray, SK and Kanwar, JR and Mukherjee, S},
title = {Advancing nanotheranostics for neuro-immunological disorders: current status and future prospects.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.08.051},
pmid = {40907816},
issn = {1873-7544},
abstract = {Neuroimmunological disorders involve complex interactions between the nervous and immune systems, leading to various severe neurological conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. These disorders are characterized by immune-mediated damage or inflammation within nervous tissue, resulting in cognitive deficits, movement issues, sensory impairments, and other neurological problems. They can affect people of all ages, but incidence increases significantly with advancing age, making them a growing public health concern. As the global population ages, the prevalence of neuroimmunological diseases is expected to rise sharply. Projections indicate that by 2050, approximately 150 million individuals worldwide may suffer from dementia-related disorders alone, with an economic burden reaching around $10 trillion. Current therapies mainly focus on symptom management, aiming to slow disease progression and improve quality of life. Emerging therapeutic strategies show promise, particularly nanomedicine, which employs nanoscale materials to deliver drugs precisely to affected tissues. This targeted approach reduces side effects and increases treatment effectiveness. Additionally, natural products and plant-based compounds are gaining attention for their neuroprotective effects, as they can modulate pathways involved in neuronal survival, repair, and immune regulation. Future research aims to deepen understanding of the molecular and genetic mechanisms underlying these disorders through advanced experimental models and technologies. These insights will facilitate the development of innovative therapies targeting neuroinflammation and immune dysregulation, with the goal of preventing disease progression or even achieving cures. Continued progress in neuroimmunology offers hope for improved treatment outcomes, reduced disease burden, and transformative advances in neurological healthcare worldwide.},
}

@article {pmid40907613,
year = {2025},
author = {Li, K and Qiu, X and Yang, Q and Wang, Z},
title = {Histone modifications: Key players in Alzheimer's disease.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112102},
doi = {10.1016/j.mad.2025.112102},
pmid = {40907613},
issn = {1872-6216},
abstract = {Alzheimer's disease (AD) is one of the most prevalent diseases in the older population. AD causes progressive cognitive and behavioral impairment, but current treatments are unable to slow or prevent the progression of this disease. Thus, identification of novel biomarkers and therapeutic targets is urgently needed. We previously described the roles of histone acetylation, crotonylation, and lactylation in the accumulation of amyloid beta and hyperphosphorylation of Tau protein, which are the hallmarks of AD. In this review, we summarize and discuss the current knowledge of the role of histone modifications in AD, with a particular emphasis on its association with characterized pathological alterations, including amyloid plaques, Tau tangles, neuroinflammation, and synaptic dysfunction. This review provides novel insights into the central role of histone modifications in AD pathogenesis and evaluates histone-modifying enzymes as potential therapeutic targets for the treatment of AD.},
}

@article {pmid40907541,
year = {2025},
author = {Wu, N and Wu, Z and Wang, P and Zhang, C and Wu, C and Huo, X and Zhang, G},
title = {Three-Dimensional Magnetic Field Measurement of Transcranial Magnetic Stimulation Using a Printed Circuit Board-Based Miniature Orthogonal Coil Array.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae0340},
pmid = {40907541},
issn = {2057-1976},
abstract = {OBJECTIVE: Transcranial magnetic stimulation (TMS) is a promising neuromodulation therapy for treating diseases such as depression and Alzheimer's disease. However, its efficacy depends on precise magnetic field targeting. Current measurement methods face a trade-off between accuracy and complexity. Their intricate designs limit miniaturization, and they are typically confined to one-dimensional detection.

APPROACH: This study proposes a miniaturized printed circuit board (PCB)-integrated coil array (11.10 mm × 9.10 mm × 1.60 mm) as a novel solution to replace complex probe systems for the synchronous measurement of three-dimensional magnetic field components (Bx, By, Bz) generated by a figure-8 coil.

RESULTS: Using this approach, we simulated and measured the magnetic field distribution produced by a self-made figure-8 coil, demonstrating consistency with relative errors below 5%, 10%, and 15% along the line of interest (LOI) in the x, y, z directions, respectively. Variations in magnetic flux density from a commercial figure-8 coil were also measured at two specific spatial positions, showing consistent trends.

SIGNIFICANCE: The presented measurement probe enables feasible characterization of TMS-induced magnetic flux, with measured values aligning closely with simulated results. By integrating orthogonal coils into a compact PCB, it overcomes the traditional accuracy-complexity trade-off. Clinically, it assists in precise coil positioning during treatment, reducing off-target side effects via magnetic field validation. Technologically, its compact and cost-effective design accelerates testing of novel TMS coils, advancing the development of efficient neuromodulation devices.},
}

@article {pmid40906916,
year = {2025},
author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT},
title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00376},
pmid = {40906916},
issn = {1948-7193},
abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.},
}

@article {pmid40904621,
year = {2025},
author = {Castilhos, RM and Formoso, CR and Borelli, WV and Teixeira, EC and Dousseau, GC and Chaves, MLF and Brucki, SMD},
title = {Anticholinergic burden and polypharmacy in patients referred from primary care to tertiary dementia centers in Brazil.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20240246},
pmid = {40904621},
issn = {1980-5764},
abstract = {UNLABELLED: Anticholinergic burden (ACB) and polypharmacy are poorly studied in the context of primary care in Brazil.

OBJECTIVE: To evaluate the ACB and polypharmacy of individuals with suspected dementia referred from primary care to tertiary dementia outpatient clinics in Brazil.

METHODS: We performed a cross-sectional study in two tertiary dementia clinics. We included individuals with suspected dementia referred from primary care. Sociodemographic variables, number of drugs, ACB score, disease duration, Mini Mental State Examination (MMSE) were collected in the first evaluation. Final diagnosis received was also collected.

RESULTS: A total of 921 individuals were included, with a median (IQR) age of 72 [64-78] years, 57.8% (532) women, 4 [2-7] years of formal education and 15 [10-20] points in MMSE. Most patients had a final diagnosis of dementia (66%, 616) and Alzheimer's disease (21.4%, 197), psychiatric disorders (16%, 147) and multifactorial dementia (14.8%, 136) were the most common diagnoses. Most individuals (68.1%, 627) were using at least one medication with anticholinergic effect, and in 44.6% (411) there was polypharmacy. ACB total score correlated with MMSE (rho=-0.13) and with total number of medications (rho=0.52). In multivariate regression, ACB score ≥1 was associated with MMSE and polypharmacy.

CONCLUSION: Most individuals referred from primary care in Brazil were using at least one medication with anticholinergic effect and this was correlated with cognitive severity. Educational measures for primary care physicians, focusing on the management of pharmacological treatment, are essential to reduce the anticholinergic load in this context.},
}

@article {pmid40904419,
year = {2025},
author = {Mullins, GR and Ardayfio, P and Gueorguieva, I and Anglin, G and Bailey, J and Chua, L and Zimmer, JA and Evans, CD and Nery, ESM and Wang, H and Khanna, R and Brooks, DA and Sims, JR},
title = {Donanemab immunogenicity in participants with early symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70149},
pmid = {40904419},
issn = {2352-8737},
abstract = {INTRODUCTION: Donanemab is an immunoglobulin G1 antibody that targets an N-terminal truncated form of amyloid beta present in mature plaques. Treatment-emergent (TE) anti-drug antibodies (ADAs) were quantified in donanemab-treated participants from two pivotal clinical trials, and effects of TE ADAs on donanemab pharmacokinetics, efficacy, and safety were assessed.

METHODS: Data were pooled from the phase 2 TRAILBLAZER-ALZ (NCT03367403) and phase 3 TRAILBLAZER-ALZ 2 trials (NCT04437511). Eligible participants were randomized 1:1 to donanemab (700 mg for the first three doses, 1400 mg thereafter) or placebo intravenously every 4 weeks up to 72 weeks. TE ADA-evaluable participants had a non-missing baseline ADA result and ≥ 1 non-missing post-baseline ADA result. TE ADA incidence and effect of titer on pharmacokinetics, amyloid plaque reduction, clinical efficacy (measured by change from baseline of integrated Alzheimer's Disease Rating Scale [iADRS] score and Clinical Dementia Rating Scale Sum of Boxes [CDR-SB]), and safety were assessed.

RESULTS: Of 922 TE ADA-evaluable donanemab-treated participants, 56 (6.1%) had ADAs detected at baseline, and 812 (88.1%) were TE ADA positive. Donanemab clearance increased linearly with logarithm of ADA titer; however, titer did not affect maximum donanemab concentration. Amyloid plaque level was significantly reduced with donanemab versus placebo, irrespective of titer (P < 0.001 for all). No association was found between ADA presence or titer and donanemab efficacy by iADRS or CDR-SB. Eighty-four of 984 (8.5%) donanemab-treated participants and 4 of 999 (0.4%) placebo-treated participants reported infusion-related reactions (IRRs). All donanemab-treated participants reporting immediate IRRs developed ADAs at some point during the study; however, 90.5% of TE ADA-positive participants did not experience IRRs.

DISCUSSION: Most participants were TE ADA positive. TE ADAs increased donanemab clearance but did not have clinically meaningful impact on plaque reduction or efficacy. While all participants reporting IRRs developed ADAs at some point during the study, the majority of participants with ADAs did not experience IRRs.

HIGHLIGHTS: In pivotal trials, most donanemab-treated participants were treatment-emergent anti-drug antibody (TE ADA) positive.TE ADAs increased donanemab clearance but did not impact plaque reduction/efficacy.All participants reporting infusion-related reactions (IRRs) developed ADAs at some point during the study.However, the majority of participants with ADAs did not experience IRRs.},
}

@article {pmid40904199,
year = {2025},
author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME},
title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70577},
doi = {10.1111/cns.70577},
pmid = {40904199},
issn = {1755-5949},
mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; },
abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases.

RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.

CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.},
}

Humans
*Exosomes/transplantation/metabolism
*Neurodegenerative Diseases/therapy
Animals
*Stem Cell Transplantation/methods/trends
*Clinical Trials as Topic/methods

@article {pmid40904091,
year = {2025},
author = {Hu, WQ and Gao, HY and Yang, L and Wang, YX and Cheng, HJ and Yang, SY and Zhang, MY and Sun, J},
title = {[Characterization of hippocampal components of Danzhi Xiaoyao Formula based on HPLC-Q-TOF-MS/MS and network pharmacology and assessment of its therapeutic potential for nervous system diseases].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {14},
pages = {4053-4062},
doi = {10.19540/j.cnki.cjcmm.20250426.201},
pmid = {40904091},
issn = {1001-5302},
mesh = {*Drugs, Chinese Herbal/chemistry/administration & dosage ; Animals ; Rats ; *Hippocampus/drug effects/chemistry/metabolism ; Network Pharmacology ; Chromatography, High Pressure Liquid ; Tandem Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; *Nervous System Diseases/drug therapy/metabolism/genetics ; Humans ; Signal Transduction/drug effects ; },
abstract = {In this study, the pharmacodynamic components and potential pharmacological functions of Danzhi Xiaoyao Formula in treating nervous system diseases were investigated by hippocampal component characterization and network pharmacology. After rats were administrated with Danzhi Xiaoyao Formula by gavage, high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) was employed to explore the components in the hippocampus of rats. Fifty-seven components were identified in the hippocampus of rats by comparing the extract of Danzhi Xiaoyao Formula, herbal components in the hippocampus after administration, and blank samples. KEGG and GO analyses predicted 74 core targets including GSK3B, MAPK1, AKT, IL6. These targets were involved in PI3K/Akt, NF-κB, MAPK, JAK/STAT, Wnt, and other signaling pathways. The results indicated that Danzhi Xiaoyao Formula may ameliorate other nervous system diseases enriched in DO, such as neurodegenerative diseases, cerebrovascular diseases, and mental and emotional disorders by mediating target pathways, inhibiting inflammation, reducing neuronal damage, and alleviating hippocampal atrophy. The relevant activities exhibited by this formula in nervous system diseases such as Alzheimer's disease, Parkinson's disease, and diabetic neuropathy have extremely high development value and are worthy of further in-depth research. This study provides a theoretical basis and practical guidance for expanding the application of Danzhi Xiaoyao Formula in the treatment of nervous system diseases.},
}

*Drugs, Chinese Herbal/chemistry/administration & dosage
Animals
Rats
*Hippocampus/drug effects/chemistry/metabolism
Network Pharmacology
Chromatography, High Pressure Liquid
Tandem Mass Spectrometry
Rats, Sprague-Dawley
Male
*Nervous System Diseases/drug therapy/metabolism/genetics
Humans
Signal Transduction/drug effects

@article {pmid40904084,
year = {2025},
author = {Pu, YZ and Chen, HF and Wang, XY and Su, C},
title = {[Caffeoylquinic acids from Erigeron breviscapus ameliorates cognitive impairment and mitochondrial dysfunction in AD by activating PINK1/Parkin-mediated mitophagy].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {14},
pages = {3969-3979},
doi = {10.19540/j.cnki.cjcmm.20250219.402},
pmid = {40904084},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism/physiopathology/psychology ; *Mitophagy/drug effects ; *Mitochondria/drug effects/metabolism/genetics ; Caenorhabditis elegans/drug effects/genetics/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism/genetics/physiopathology ; Rats ; *Protein Kinases/metabolism/genetics ; Humans ; Male ; Disease Models, Animal ; Caenorhabditis elegans Proteins/metabolism/genetics ; *Drugs, Chinese Herbal/administration & dosage ; },
abstract = {This study aimed to investigate the effects of caffeoylquinic acids from Erigeron breviscapus(EBCQA) on cognitive impairment and mitochondrial dysfunction in Alzheimer's disease(AD), and to explore its underlying mechanisms. The impacts of EBCQA on paralysis, β-amyloid(Aβ) oligomerization, and mRNA expression of mitophagy-related genes [PTEN-induced putative kinase 1(PINK1) homolog-encoding gene pink-1, Parkin homolog-encoding gene pdr-1, Bcl-2 interacting coiled-coil protein 1(Beclin 1) homolog-encoding gene bec-1, microtubule-associated protein 1 light chain 3(LC3) homolog-encoding gene lgg-1, autophagic adapter protein 62(p62) homolog-encoding gene sqst-1] were examined in the AD Caenorhabditis elegans CL4176 model, along with mitochondrial functions including adenosine triphosphate(ATP) content, enzyme activities of mitochondrial respiratory chain complexes Ⅰ,Ⅲ, and Ⅳ, and mitochondrial membrane potential. Additionally, the effects of EBCQA on the green fluorescent protein(GFP)/red fluorescent protein from Discosoma sp.(DsRed) ratio, the expression of phosphatidylethanolamine-modified and GFP-labeled LGG-1(PE-GFP::LGG-1)/GFP-labeled LGG-1(GFP::LGG-1), and GFP-labeled SQST-1(GFP::SQST-1) proteins were investigated in transgenic C. elegans strains. The effect of EBCQA on paralysis was further evaluated after RNA interference(RNAi)-mediated suppression of the pink-1 and pdr-1 genes in CL4176 strain. An AD rat model was established through intraperitoneal injection of D-galactose and intragastric administration of aluminum trichloride. The effects of β-nicotinamide mononucleotide(NMN) and EBCQA on learning and memory ability, neuronal morphology, mitophagy occurrence, mitophagy-related protein expression(PINK1, Parkin, Beclin 1, LC3-Ⅱ/LC3-Ⅰ, p62), and mitochondrial functions(ATP content; enzyme activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ; mitochondrial membrane potential) were investigated in this AD rat model. The results showed that EBCQA delayed paralysis onset in the CL4176 strain, reduced Aβ oligomer formation, and upregulated the mRNA expression levels of lgg-1, bec-1, pink-1, and pdr-1, while downregulating sqst-1 mRNA expression. EBCQA also enhanced ATP content, mitochondrial membrane potential, and the activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ. Furthermore, EBCQA improved the PE-GFP::LGG-1/GFP::LGG-1 ratio, reduced GFP::SQST-1 expression, and decreased the GFP/DsRed ratio. Notably, the ability of EBCQA to delay paralysis was significantly reduced following RNAi-mediated suppression of pink-1 and pdr-1 in CL4176 strain. In AD rats, the administration of NMN or EBCQA significantly improved learning and memory, restored neuronal morphology in the hippocampus, increased autophagosome numbers, and upregulated the expression of PINK1, Parkin, Beclin 1, and the LC3-Ⅱ/LC3-Ⅰ ratio, while reducing p62 expression. Additionally, the treatment with NMN or EBCQA both elevated ATP content, mitochondrial respiratory chain complex Ⅰ, Ⅲ, and Ⅳ activities, and mitochondrial membrane potential in the hippocampus. The above findings indicate that EBCQA improves cognitive impairment and mitochondrial dysfunction in AD, possibly through activation of PINK1/Parkin-mediated mitophagy.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/metabolism/physiopathology/psychology
*Mitophagy/drug effects
*Mitochondria/drug effects/metabolism/genetics
Caenorhabditis elegans/drug effects/genetics/metabolism
*Ubiquitin-Protein Ligases/metabolism/genetics
*Cognitive Dysfunction/drug therapy/metabolism/genetics/physiopathology
Rats
*Protein Kinases/metabolism/genetics
Humans
Male
Disease Models, Animal
Caenorhabditis elegans Proteins/metabolism/genetics
*Drugs, Chinese Herbal/administration & dosage

@article {pmid40903965,
year = {2025},
author = {Parikh, A and Cholavaram, A and Chitti Babu, AK and Deepankumar, K and Vijayan, M},
title = {Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00368},
pmid = {40903965},
issn = {1673-5374},
abstract = {Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltage-dependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltage-dependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.},
}

@article {pmid40903964,
year = {2025},
author = {Wu, S and Guo, T and Zheng, X and Gu, C and Hu, Y and Gu, X and Zhou, X},
title = {Integrated machine learning-based RNA sequencing and single-cell analysis reveal RNA methylation regulation patterns in the immune microenvironment of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01650},
pmid = {40903964},
issn = {1673-5374},
abstract = {Alterations in RNA methylation may affect the initiation and development of Alzheimer's disease. However, the exact nature of the relationship between RNA methylation and Alzheimer's disease remains unclear. In this study, RNA methylation levels were analyzed by bulk transcriptomic and single-cell RNA sequencing. The expression levels of RNA methylation regulators were confirmed using molecular biology techniques. Co-expression network analysis was used to identify relevant long non-coding RNAs. Molecular subtypes related to RNA methylation were classified, and variations in clinical characteristics, biological behavior, and immune signatures between subtypes were assessed. Machine learning approaches were applied to identify methylation-associated long noncoding RNAs, which were used to construct a risk model and nomogram for Alzheimer's disease. Potential therapeutic agents for different risk groups were predicted, and in vitro experiments were conducted to identify key RNA methylation events. Single-cell analysis demonstrated enhanced RNA methylation in patients with Alzheimer's disease, particularly within T cells, B cells, and NK cells. Quantitative reverse transcription-polymerase chain reaction and western blot confirmed alterations in RNA methylation regulators in neurons treated with amyloid-β oligomers in vitro. This evidence supported the classification of patients with Alzheimer's disease into heterogeneous subtypes. Specifically, subtype 1 was identified as the immune-active subtype, while subtype 2 was characterized by a metabolic phenotype. Machine learning algorithms identified five significant methylation-associated long non-coding RNAs -LINC01007, MAP4K3-DT, MIR302CHG, VAC14-AS1, and TGFB2-OT1-that accurately predict clinical outcomes for patients with Alzheimer's disease. These patients were classified into low- and high-risk categories; the latter group displayed higher immune infiltration, upregulated immune regulatory gene expression, and elevated immune scores and responded better to treatment with arachidonic-trifluoroethane. These findings suggest that dysregulated RNA methylation alters the immune microenvironment in Alzheimer's disease and is closely associated with its progression. This phenomenon provides novel insights into potential therapeutic strategies for Alzheimer's disease that target RNA methylation.},
}

@article {pmid40903963,
year = {2025},
author = {Fan, F and Zhao, N and Guo, M},
title = {Lymphatic-venous anastomosis: Cracking the code of Alzheimer's disease treatment?.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00540},
pmid = {40903963},
issn = {1673-5374},
}

@article {pmid40903956,
year = {2025},
author = {Chen, Y and Yin, P and Chen, Q and Zhang, Y and Tang, Y and Jin, W and Yu, L},
title = {Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00274},
pmid = {40903956},
issn = {1673-5374},
abstract = {Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system. Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide. Therefore, it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies. In recent years, increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process. The central and peripheral immune systems exert different roles in the disease progression. The development of neurodegenerative diseases is influenced by interactions between them. This review focuses on how the immune system, including microglia mediated nucleotide-binding oligomerization domainlike receptor protein 3 inflammation activation and T cell-mediated neuroinflammation, interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability. Besides, we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway. Insight into the immune system's functions and cellular interactions is essential for progressing disease research. In addition, the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment. Therefore, this review summarizes some of the existing treatment strategies for amyloid-beta, tau, neuroinflammation, α-synuclein, associated microbiota, immune modulation, and neural injury repair. In addition, this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress. In view of the current research status, new research directions and suggestions are proposed.},
}

@article {pmid40903950,
year = {2025},
author = {Liu, Y and Tang, T and Cai, H and Liu, Z},
title = {Bidirectional communication between the gut microbiota and the central nervous system.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00434},
pmid = {40903950},
issn = {1673-5374},
abstract = {In recent years, an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system. This communication occurs through the microbiota-gut-brain axis. As people age, the composition of the gut microbiota undergoes considerable changes, which are now known to play an important role in the development of many neurodegenerative diseases. This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain. It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation, maintaining gut health, and influencing the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders, including fecal microbiota transplantation, probiotics, and prebiotics. Many studies show that the gut microbiota affects the brain in several ways. For example, it can produce substances such as short-chain fatty acids and activate inflammatory pathways. Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems. Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism's health. Microorganisms primarily colonize the gut and are involved in host nutrient metabolism, maintaining the structural integrity of the intestine, preserving the intestinal mucosal barrier, and modulating the immune system. The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis. The composition of the gut flora changes considerably with age, and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging. Recent studies have linked these changes to a variety of age-related neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and Huntington's disease. Specifically, the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways. In preclinical studies, targeted modulation of the gut microbiota, through methods such as fecal microbiota transplantation, probiotics, and prebiotics, has demonstrated potential in improving host behavioral outcomes. Therefore, gut microbiotabased treatments offer new hope for the treatment of nervous system diseases. However, due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies, researchers need to carefully assess their safety and efficacy before widespread clinical application.},
}

@article {pmid40903895,
year = {2025},
author = {Higgins, A and Tewolde, S and Page, SD and Rubenstein, E},
title = {The Occurrence of Obstructive Sleep Apnea and Its Association With Alzheimer Dementia in Medicaid-Enrolled Adults With Down Syndrome, 2011-2019.},
journal = {American journal of medical genetics. Part A},
volume = {},
number = {},
pages = {e64241},
doi = {10.1002/ajmg.a.64241},
pmid = {40903895},
issn = {1552-4833},
support = {R01AG073179/AG/NIA NIH HHS/United States ; },
abstract = {Down syndrome is a condition caused by trisomy of chromosome 21 and is the most common genetic cause of intellectual disability. Due to distinct body and facial morphology, people with Down syndrome appear to be at increased risk for obstructive sleep apnea (OSA). Additionally, adults with Down syndrome are at increased risk for Alzheimer dementia at younger ages than the general population, and OSA has been identified as a risk factor for Alzheimer dementia in the general population. This study aims to explore the prevalence of diagnosed OSA, as well as the association between OSA and Alzheimer dementia, in adults with Down syndrome using Medicaid claims data from2011 to 2019. Of 118,539 adults with Down syndrome who met inclusion criteria, 23,785 had at least one OSA claim from2011 to 2019 (20.1%, 95% CI 19.8%-20.3%). After weighting for age, sex, dual enrollment, race, ethnicity, and region, adults with Down syndrome and OSA claims had 1.08 times the hazard of having a claim for Alzheimer dementia compared to those without OSA claims (95% CI 1.05-1.10). OSA is common in adults, and our findings have clinical implications for its evaluation and treatment in those with Down syndrome.},
}

@article {pmid40903623,
year = {2025},
author = {Anzai, Y and Minoshima, S},
title = {The role of brain MR and FDG-PET in the diagnosis of neurodegenerative disease.},
journal = {European radiology},
volume = {},
number = {},
pages = {},
pmid = {40903623},
issn = {1432-1084},
abstract = {Alzheimer disease (AD) is the most common dementing disorder, affecting 55 million people worldwide. Brain MRI plays an integral role in the diagnostic evaluation of patients with cognitive symptoms. When interpreting brain MRI for cognitive impairment, radiologists should assess the following four key features: (1) white matter ischemic burden, (2) structural changes to suggest normal pressure hydrocephalus, (3) locoregional pattern of brain atrophy, and (4) presence of microhemorrhage or superficial siderosis, particularly for determining eligibility for anti-amyloid monoclonal antibody (MAB) treatment when appropriate. The recent approval and clinical adoption of anti-amyloid MAB expanded the role of neuroradiologists in evaluating eligibility and monitoring ARIA (amyloid-related imaging abnormality) among patients receiving anti-amyloid MAB. This advancement underscores the importance of standardized imaging protocols and effective communication between neuroradiologists and cognitive neurologists. Depending on the severity of ARIA and patients' symptoms, treatment may need to be suspended or discontinued. This review article explores brain MRI and FDG-PET/CT imaging abnormalities in patients with major cognitive and movement disorders associated with dementia. It aims to assist radiologists in providing differential diagnoses within a clinical context. Finally, the article emphasizes the importance of recognizing co-pathologies, since patients may have more than one neurodegenerative disease rather than viewing these neurodegenerative diseases as being mutually exclusive. KEY POINTS: Question Traditional regional patterns of brain atrophy on MRI by neuroradiologists may not be effective given the recent advances in understanding of neurodegenerative disease and recognition of co-pathologies. Findings The locoregional atrophy and the patterns of metabolic abnormality help in the differential diagnosis of neurodegenerative disease. Remember that brain MRI determines eligibility for anti-amyloid immunotherapy. Clinical relevance Understanding clinical history is vital for interpreting brain MRI for patients with cognitive impairment or memory loss. Newly recognized entities such as limbic-predominant age-related TDP43 encephalopathy (LATE) can mimic Alzheimer disease among extremely elderly patients with amnestic symptoms with mesial temporal lobe atrophy.},
}

@article {pmid40903613,
year = {2025},
author = {Horn, A and Neumann, WJ},
title = {From adaptive deep brain stimulation to adaptive circuit targeting.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40903613},
issn = {1759-4766},
abstract = {Deep brain stimulation (DBS) substantially improves motor symptoms and quality of life in people with movement disorders such as Parkinson disease and dystonia, and it is also being explored as a treatment option for other brain disorders, including treatment-resistant obsessive-compulsive disorder, Alzheimer disease and depression. Two major developments are currently driving progress in DBS research: first, the framework of adaptive DBS, which senses brain activity to infer the momentary state of the symptoms of a patient and reacts by adapting stimulation settings, and second, the concept of connectomic DBS, which identifies brain circuits that should optimally be stimulated to reduce specific symptoms. In this Perspective, we propose a unified framework that combines these two concepts. Our approach, termed adaptive circuit targeting, decodes symptom severity from brain signals and adaptively activates the most relevant symptom-response circuits. We discuss the state of the art in the adaptive and connectomic DBS fields and the research gaps that need to be addressed to unify these concepts.},
}

@article {pmid40903459,
year = {2025},
author = {Zhang, B and Zhang, S and Guo, Z and Hong, C and Zhang, F and Lin, H},
title = {Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {341},
pmid = {40903459},
issn = {2158-3188},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects/physiopathology ; *Nucleobindins/metabolism ; *Cellular Senescence/drug effects ; *Alzheimer Disease/metabolism/physiopathology ; Mice ; *Endothelial Cells/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Peptide Fragments ; Brain/metabolism ; Mice, Transgenic ; Male ; Disease Models, Animal ; Humans ; },
abstract = {Cellular senescence and associated endothelial permeability are crucial factors in the dysfunction of the blood-brain barrier (BBB) in neurodegenerative diseases, including Alzheimer's disease (AD). Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized Aβ1-42. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized Aβ1-42. Notably, NF-1 reduced oligomerized Aβ1-42-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized Aβ1-42. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized Aβ1-42-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.},
}

Animals
*Blood-Brain Barrier/metabolism/drug effects/physiopathology
*Nucleobindins/metabolism
*Cellular Senescence/drug effects
*Alzheimer Disease/metabolism/physiopathology
Mice
*Endothelial Cells/metabolism/drug effects
Amyloid beta-Peptides/metabolism
Peptide Fragments
Brain/metabolism
Mice, Transgenic
Male
Disease Models, Animal
Humans

@article {pmid40902672,
year = {2025},
author = {Sharma, S and Bashir, B and Kolekar, KA and Acharya, A and Gupta, M and Jena, R and Vishwas, S and Kaur, J and Gupta, G and Kumbhar, PS and Patle, D and Chaitanya, M and Gulati, M and Singh, SK},
title = {Tailoring the biomarkers of Alzheimer's disease using a gut microbiome-centric approach: Preclinical, clinical, and regulatory perspectives.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102888},
doi = {10.1016/j.arr.2025.102888},
pmid = {40902672},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to its complex etiology and limited treatment options. Traditional pharmacotherapies targeting amyloid-β (Aβ) and cholinergic pathways offer modest benefits and are often associated with adverse effects. Emerging evidence implicates gut dysbiosis and the gut-brain axis in the pathogenesis and progression of AD. This review explores the multifactorial pathophysiology of AD and evaluates the therapeutic potential of gut-based interventions such as probiotics, prebiotics, synbiotics, metabiotics, postbiotics, and fecal microbiota transplantation (FMT) in mitigating disease pathology. Emphasis has also been given on role of miRNA released from FMT in management of AD. Preclinical and clinical studies demonstrate that these strategies can restore microbial homeostasis, reduce neuroinflammation, enhance gut barrier integrity, and improve cognitive outcomes. The regulatory aspects with use of probiotics based products and FMT is also highlighted. The modulation of neuroimmune, neuroendocrine, and neural pathways through microbiota-derived metabolites offers a promising avenue for AD management. Despite encouraging findings, further research is needed to address interindividual microbiome variability, delivery challenges, and the requirement for large-scale, randomized trials. Personalized gut-targeted approaches may open new horizons for the prevention and treatment of AD.},
}

@article {pmid40901302,
year = {2025},
author = {Stothart, G and Alderman, S and Hermann, O and Creavin, S and Coulthard, EJ},
title = {A passive and objective measure of recognition memory in mild cognitive impairment using Fastball memory assessment.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf279},
doi = {10.1093/braincomms/fcaf279},
pmid = {40901302},
issn = {2632-1297},
abstract = {As viable pharmacotherapies and blood biomarkers emerge for dementia treatment and screening, there remains a great need for accurate, sensitive biomarkers of cognitive function. We have previously demonstrated that Fastball, a new Electroencephalography (EEG) method for the passive and objective measurement of recognition memory that requires no behavioural memory response or task comprehension, is sensitive to cognitive dysfunction in Alzheimer's disease. Here we present new evidence that Fastball is sensitive to amnestic dysfunction in an earlier stage of the dementia lifecourse, Mild Cognitive Impairment (MCI). 53 MCI patients and 54 healthy older adult (HOA) controls completed a 3-min Fastball task in which they passively viewed rapidly presented images while EEG captured their automatic ability to differentiate between images based on previous exposure. They also completed neuropsychological assessments of memory (Delayed Match to Sample-48), sustained attention (Psychomotor Vigilance Task), and general cognitive function (Addenbrookes Cognitive Exam-iii). Participants were re-tested after 1 year to establish the test-retest reliability of Fastball in HOAs, and the sensitivity of Fastball to cognitive decline in MCI patients, over a 1 year period. Amnestic MCI patients showed significantly reduced Fastball responses compared with non-amnestic MCI patients (P = 0.001, Cohen's d = 0.98) and HOA controls (P = 0.005, Cohen's d = 0.64). Regression analyses showed that Fastball EEG responses were selectively predictive of neuropsychological measures of recognition memory and not attention. Between baseline and year one follow-up Fastball showed moderate to good test-retest reliability in HOA controls, and the six MCI-dementia converters showed a trend for lower Fastball responses at baseline which will be confirmed with further longitudinal assessment. Fastball is further validated as a viable method for testing recognition memory in cognitively impaired populations. We have demonstrated that it is selectively predictive of memory dysfunction and not attention or other cognitive functions. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball is a viable functional biomarker that can help to advance cognitive assessment in MCI.},
}

@article {pmid40899945,
year = {2025},
author = {Saido, TC and Iwata, N},
title = {The tale of donanemab: God is in the details.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251371240},
doi = {10.1177/13872877251371240},
pmid = {40899945},
issn = {1875-8908},
abstract = {Alzheimer's disease is a major cause of dementia, that affects approximately 7-8% of people aged 65 years and older (according to WHO & Alzheimer's Disease International) and thus is a major concern in public health world-wide. This review chronicles the foundational research and translational trajectory leading to the development of donanemab, a monoclonal antibody targeting pyroglutamyl amyloid-β (Aβ3pE-X) peptides, recently approved for the treatment of early Alzheimer's disease (AD). We trace a 30-year arc from the biochemical identification of Aβ species to the recognition of Aβ3pE-42 as a predominant pathological isoform in AD and Down syndrome brains-a fact still underrecognized among clinicians and researchers. We highlight key breakthroughs in antibody generation, Aβ peptide biochemistry, and resistance to enzymatic degradation. Mechanistic distinctions between donanemab (Kisunla[®]), and lecanemab (Leqembi[®]) are also explored, along with therapeutic implications for targeting specific Aβ species at preclinical stages of disease. The review emphasizes how persistent biochemical research, fueled by intellectual curiosity, serendipity, and rigorous experimentation, has culminated in clinical proof-of-concept for the amyloid hypothesis. In addition to its molecular specificity, donanemab's development underscores a critical shift toward precision medicine in Alzheimer's care. Its clinical validation, though limited in scope, reinforces the need for scalable and affordable interventions that can address the growing global burden of dementia. We expect these therapeutic antibodies to contribute to reducing the global burden by ceasing the disease progression in a preclinical stage now that new methods for fluid biomarkers are becoming available. As the global population ages, understanding and addressing AD has become a top priority in neuroscience and public health.},
}

@article {pmid40899340,
year = {2025},
author = {Zamanian, MY and Khachatryan, LG and Heidari, M and Darabi, R and Golmohammadi, M and Al-Aouadi, RFA and Akkol, EK},
title = {The Therapeutic Potential of Flavonols in Alzheimer's Disease: Inhibiting Amyloid-β, Oxidative Stress, and Neuroinflammation.},
journal = {BioFactors (Oxford, England)},
volume = {51},
number = {5},
pages = {e70047},
doi = {10.1002/biof.70047},
pmid = {40899340},
issn = {1872-8081},
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics ; *Flavonols/pharmacology/therapeutic use ; Animals ; Kaempferols/pharmacology ; Flavonoids/pharmacology ; *Neuroprotective Agents/pharmacology ; Quercetin/pharmacology ; Mice ; Humans ; Male ; Mitochondria/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Signal Transduction/drug effects ; Amyloid Precursor Protein Secretases/genetics/metabolism ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, oxidative stress, and neuroinflammation, remains a significant global health challenge. This study investigates the therapeutic potential of flavonols-quercetin, kaempferol, myricetin, and fisetin-in targeting Aβ aggregation and mitigating AD pathology through diverse molecular mechanisms. Our findings reveal that flavonols effectively inhibit Aβ oligomerization and fibril formation, reduce oxidative stress via Nrf2/HO-1 pathway activation, and suppress neuroinflammation by modulating microglial polarization. Additionally, these compounds enhance mitochondrial function, promote autophagy-mediated clearance of Aβ aggregates, and regulate key enzymes such as β-secretase (BACE1) and α-secretases (ADAM10/17), favoring non-amyloidogenic pathways. Quercetin demonstrated neuroprotective effects by activating TrkB signaling, reducing tau phosphorylation, and enhancing synaptic plasticity. Kaempferol prevented Aβ-induced apoptosis via the ER/ERK/MAPK pathway and inhibited acetylcholinesterase activity, improving cognitive outcomes. Myricetin ameliorated mitochondrial dysfunction and oxidative damage through GSK3β/ERK2 signaling modulation and showed enhanced brain bioavailability when delivered via nanostructured lipid carriers. Fisetin reduced Aβ burden by upregulating neprilysin expression, suppressed neuroinflammation, and improved synaptic function by restoring synaptic protein levels. Overall, flavonols exhibit multi-targeted therapeutic potential against AD by addressing its complex pathogenesis. Their ability to cross the blood-brain barrier and low toxicity profiles position them as promising candidates for further clinical development. This study underscores the potential of flavonols as natural agents for AD treatment and highlights their role in advancing multi-mechanistic therapeutic strategies.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology/genetics
Oxidative Stress/drug effects
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics
*Flavonols/pharmacology/therapeutic use
Animals
Kaempferols/pharmacology
Flavonoids/pharmacology
*Neuroprotective Agents/pharmacology
Quercetin/pharmacology
Mice
Humans
Male
Mitochondria/drug effects
*Neuroinflammatory Diseases/drug therapy
Signal Transduction/drug effects
Amyloid Precursor Protein Secretases/genetics/metabolism